Medicinal Chemistry · Medicinal Chemistry archive
Medicinal Chemistry — October 2026
2026-10-23 4 articles
Why BRD9 PROTACs underperform in mice, and a humanized-E3 fix
- Widely used CRBN- and VHL-based BRD9 degraders such as dBRD9 and VZ185 are much less potent in mouse cells, even though BRD9 itself is highly conserved.
- The gap points to species differences in the E3 ligases, notably the Crbn I391 residue and structural variation in VHL, which likely hamper ternary complex formation.
- Expressing human CRBN or VHL, or introducing a CrbnI391V mutation, restored potency in mouse cells and improved BRD9 degradation in vivo.
Anyone who has watched a PROTAC look great in human lines and flat in a mouse efficacy study will recognize this. It is a reminder that degrader PK/PD in rodents can fail for E3 reasons rather than compound reasons, so a CrbnI391V or humanized-E3 model is worth setting up early. It also argues for profiling ternary complex formation across species before reading a negative in vivo result as a dead series.
Improving PROTAC-Mediated Degradation in Mouse Models: BRD9 as a Case Study ↗
Pyrroloquinoline antitubulin agents keep activity in paclitaxel- and daunorubicin-resistant cells
- A library of 1H-pyrrolo[3,2-c]quinolines was made and mapped by SAR, yielding compounds with low-nanomolar antiproliferative potency and very large selectivity over normal fibroblasts.
- The best derivatives kept activity in daunorubicin- and paclitaxel-resistant sublines and showed low efflux ratios, suggesting limited cross-resistance.
- A lead showed rapid absorption, moderate half-life and limited brain penetration, but zebrafish embryo toxicity pointed to a narrow therapeutic window.
Tubulin binders that dodge P-gp efflux are always of interest, and low efflux ratios plus retained activity in resistant lines is the right first filter. The zebrafish result is the honest sting in the tail: potent antimitotics often have a thin margin, so selectivity over fibroblasts in culture will not settle the safety question. I would look next at the binding site and how far the scaffold can be tuned toward a wider window.
An oral STING inhibitor that blocks palmitoylation shows efficacy in inflammation models
- Researchers built a tetrahydropyrazolo[1,5-a]pyrazine series as inhibitors of STING, the innate-immune adaptor behind several interferonopathies and autoimmune conditions.
- The lead, compound 37, combined strong cellular STING inhibition with good oral exposure and a clean safety read.
- Mechanistically it prevents STING palmitoylation, which in turn shuts down downstream signaling.
- Oral dosing reduced inflammation in acute chemical-challenge and Trex1-deficient mouse models, among others.
STING inhibitors have mostly been tool compounds or covalent binders, so a non-covalent-looking, orally dosed chemotype that acts by blocking palmitoylation is a different handle on the target. I would want to know whether it truly binds the Cys91 pocket or acts upstream, because that decides selectivity versus other palmitoylated proteins. The Trex1 mouse data is the convincing part for an autoimmune indication.
Designing out a BRD4 liability from dual TLR7/8 antagonists for lupus
- Structure-based optimization of 2-(pyridin-2(1H)-one)indoles gave dual TLR7/8 antagonists with better permeability, less ion-channel activity and lower volume of distribution than the earlier series.
- Early pyridone leads unexpectedly suppressed immune-cell proliferation, which the team traced to a hypothesized BRD4 off-target.
- Optimizing away BRD4 binding removed the anti-proliferative effect while keeping potent inhibition of TLR7/8-driven IL-6 in human whole blood.
This is a tidy example of phenotype-led off-target triage: odd toxicity in cell panels, a mechanistic guess, then SAR that separates the two activities. Endosomal TLR7/8 antagonists need to be both cell-permeable and cleanly selective, and BRD4 is an easy trap for flat heteroaromatics. I would check the pyridone's binding mode in the TLR7/8 dimer interface before borrowing the fix for other scaffolds.
2026-10-22 6 articles
Inhaled-by-design pyrrolopyrimidine DDR1/2 inhibitors target pulmonary fibrosis
- Structure-based design delivered two 5:6 heterocyclic series with strong DDR1/DDR2 affinity and a promising kinome selectivity profile.
- An inhaled-by-design strategy then tuned potency, physicochemical and in vitro ADME properties toward lung-restricted compounds.
- Compound 25 combined antifibrotic activity in a TGF-β-induced in vitro fibrosis model with a favorable pharmacokinetic profile for local delivery.
Inhaled kinase inhibitors live or die on lung retention versus systemic clearance, and designing for that from the start is the right call rather than retrofitting a systemic compound. The pitfalls I'd watch are lysosomal trapping and mucociliary clearance, which in vitro ADME rarely captures. DDR biology is compelling in fibrosis, but it's still a target waiting for clinical validation.
Lung-Tailored Pyrrolo-pyrimidine DDR Inhibitors Designed for Optimized Local Delivery ↗
Macrocyclic pyrazolotriazine CDK7 inhibitor combines kinome-wide selectivity with oral exposure
- Structure-based optimization of a 17-membered macrocyclic pyrazolo-triazine scaffold gave a potent CDK7 inhibitor.
- It showed no significant off-target activity across a panel of more than 400 kinases, addressing the poor selectivity of earlier CDK7 inhibitors.
- In cells it caused cell-cycle arrest, suppressed transcription and lowered c-Myc, especially in triple-negative breast cancer lines, with oral bioavailability and linear PK.
A clean result across 400+ kinases is rare for CDK7, where the covalent field has leaned on THZ-type warheads. A non-covalent macrocycle that is also orally exposed is the profile I'd actually want to pick up for a transcriptional-addiction indication. The open question is on-target toxicity, since selectivity among kinases won't spare you CDK7's role in normal transcription.
Non-ATP-competitive MKK3 modulators suppress TNF-α in mouse colitis models
- ATP-competitive p38 inhibitors failed in the clinic partly through poor kinome selectivity, so the authors targeted the upstream kinase MKK3 through a non-ATP-competitive pocket.
- The lead, (R)-48, suppressed TNF-α production, was highly orally bioavailable and showed dose-dependent efficacy with clear PK/PD relationships in mouse ulcerative colitis models.
- Biophysical data (HDX-MS) were used to probe how the compounds engage MKK3.
Moving one node upstream of p38 is a sensible way around the selectivity problem that sank the first-generation inhibitors. An oral, TNF-lowering small molecule for UC would be a genuinely different option next to injectable biologics. My concern is the allosteric pocket: SAR for non-ATP-site kinase binders can be steep and hard to translate between species, so I'd check the human-protein data early.
Fumarate-tagged TTK inhibitor turns into a monovalent degrader via RNF126
- Appending an electrophilic monomethyl fumarate handle to a TTK inhibitor gave a single-warhead degrader, with no E3 ligand attached.
- The lead compound drove TTK degradation and showed stronger antiproliferative activity than the parent inhibitor across several cancer cell lines.
- Mechanistic work points to the E3 ligase RNF126, which the compound stabilizes in complex with TTK, leading to ubiquitination and proteasomal turnover.
Monovalent degraders are attractive because you keep the molecular weight and permeability of a plain inhibitor. The catch is that a fumarate handle is a cysteine-reactive group, so I'd want proteome-wide reactivity data before believing RNF126 is the whole story. Still, if the handle transfers across kinase scaffolds, it's a cheap trick to try on any inhibitor series you already own.
Electrophile-first screen yields covalent aminothiazole inhibitors of the E2 enzyme UBE2D2
- An electrophile-first screen, combined with X-ray crystallography, found a covalent hit that engages two cysteines (C85 and C111) of UBE2D2.
- Structure-guided SAR on the amide and ester groups removed binding to C111 while improving engagement of C85.
- The optimized analog inhibited UBE2D2 activity in vitro and suppressed proliferation of A549 lung cancer cells.
E2s have long been written off as undruggable, so seeing a crystal-supported covalent series is a real step. The interesting design move is dialing out the second cysteine, which is exactly what you need before calling anything a probe. I'd now ask how it behaves across other UBE2D family members, since the active-site cysteine is conserved and selectivity will be the hard part.
YKS-34: a PDE4B inhibitor with >1000-fold isoform selectivity for pulmonary fibrosis
- The authors set out to improve on the only approved PDE4B-preferential drug, nerandomilast, which is only about 9-fold selective over PDE4D.
- YKS-34 is a potent PDE4B inhibitor with more than 1000-fold selectivity over PDE4A, PDE4C and PDE4D.
- It suppressed TGF-β-driven fibroblast activation and LPS-induced TNF-α release in vitro, and showed favorable PK with accumulation in lung tissue.
PDE4D inhibition is what drives nausea and vomiting, so going from 9-fold to over 1000-fold is the right kind of optimization to chase. The pocket differences between B and D are tiny, which makes me curious what the binding mode looks like. I'd want to see this in a bleomycin model with a therapeutic dosing regimen before getting too excited.
2026-10-21 4 articles
A DNA-based PROTAC degrades CENPB in TKI-resistant lung cancer models
- CENPB, the sequence-specific DNA-binding protein at centromeres, is overexpressed in aggressive cancers, yet has no direct inhibitors.
- CENPB OligoTAC links a CENPB-binding oligodeoxynucleotide to an E3 ligase ligand, driving CENPB ubiquitination and proteasomal degradation, centromere disruption and apoptosis.
- It was active in NSCLC models resistant to first-, second- and third-generation TKIs, with little toxicity to normal cells, good serum stability and a favorable in vivo PK and tolerability profile.
Using the protein's own DNA recognition sequence as the warhead sidesteps the need for a small-molecule pocket, which is the appeal for transcription-factor-like targets. The open questions I would press on are delivery beyond mouse models, oligonucleotide manufacturing cost, and whether the selectivity for tumor over normal cells holds up when CENPB is expressed everywhere.
Centromere-Targeting Chimeras for Combating Cancer Drug Resistance ↗
Dialing hERG out of a DCN1–UBE2M inhibitor without losing potency
- The earlier tool compound NAcM-OPT blocked the DCN1–UBE2M interaction, was orally available and slowed xenograft growth, but carried significant hERG affinity that stalled development.
- The authors systematically modified the scaffold to cut hERG binding while keeping DCN1 engagement.
- Lead compound 110 matched the parent in biochemical and cellular potency, with better physicochemical properties and improved selectivity against hERG.
This is the unglamorous but necessary second act: a validated PPI chemotype that was dead on cardiac safety, rescued by SAR alone. The takeaway for anyone with a basic, lipophilic PPI binder is that hERG can often be engineered out without giving up the pharmacophore, so check your own series before abandoning it.
Perspective: how structure-guided design finally delivered FGFR3-selective inhibitors
- Second-generation pan-FGFR inhibitors proved the concept but were limited by toxicities from inhibiting FGFR1, FGFR2 and FGFR4.
- Despite high structural homology across the family, structure-guided work has produced the first FGFR3-selective inhibitors to reach clinical evaluation.
- The Perspective covers the biological rationale, the design strategies behind the selectivity and emerging indications, including bladder cancer and achondroplasia.
Isoform selectivity inside a highly conserved kinase family is a good test of how far structure-based design really goes, and FGFR3 now has clinical-stage answers. The achondroplasia angle is the interesting one: a chronic, pediatric-adjacent indication raises the tolerability bar far above oncology, which is exactly where selectivity pays off.
A pyrazine-2-carboxamide antimalarial that cures mice in one dose has entered phase 1
- A P. falciparum growth-inhibition screen identified a new pyrazine-2-carboxamide series for blood-stage malaria.
- Lead optimization improved anti-plasmodial potency and metabolic stability and reduced CYP2D6 inhibition risk, giving IWY357.
- A single dose was fully curative in a Pf-humanized SCID mouse model, resistance selection showed a high barrier, and the compound has progressed through GLP toxicology into phase 1.
A phenotypic hit taken all the way to the clinic with a single-dose cure in the humanized-mouse model is what the field has wanted since resistance to front-line agents began eroding. The CYP2D6 fix matters for combinations, which is where a short-course regimen would actually live. I would watch the human PK, since a single-dose claim lives or dies on exposure.
2026-10-20 4 articles
Epoxysuccinamide warheads hit SARS-CoV-2 PLpro hard, but a hydrazide linker undermines them
- Covalent PLpro inhibitors were designed by combining an epoxysuccinamide warhead for Cys-111 with groove-binding features borrowed from non-covalent inhibitors.
- The compounds showed very high enzymatic potency and strongly reduced viral titres in cell culture.
- The flexible hydrazide linker was cleaved by hepatic carboxylesterases, and alternative linkers did not work, so the series is metabolically limited.
A potent warhead that dies in the liver is a familiar story, and here the culprit is the very linker the chemistry needs for Cys-111 reach. I'd still keep the epoxysuccinamide in the toolbox for the next coronavirus, but the linker would be the first thing I'd redesign.
Discovery of Epoxysuccinates as Potent Covalent Inhibitors of SARS-CoV-2 Papain-like Protease ↗
Replacing saruparib's carboxamide yields an oral, brain-penetrant PARP1-selective inhibitor
- Aimed at CNS malignancies, the program replaced the carboxamide of saruparib with a series of heterocycles, targeting PARP1 over PARP2 to limit haematological toxicity.
- Caco-2 efflux, rather than the usual MDR1-MDCK assay, was used as a progression filter to select compounds with good unbound brain exposure.
- The lead compound was orally bioavailable and caused tumour regression in xenografts at a low dose, with a projected low clinical dose.
Swapping the primary carboxamide is a bold move, since that group anchors the nicotinamide pocket, and the heterocycles evidently kept the binding. The more useful lesson is the filter: if Caco-2 efflux predicts unbound brain exposure better than MDR1-MDCK, plenty of CNS programs may be discarding good compounds.
Much of the PROTAC target-engagement spread is exposure, not E3 recognition
- Twenty PROTACs with varied E3 ligands, linkers and target binders were profiled in intracellular NanoBRET competition assays against cereblon and VHL tracers.
- Apparent potency spread widely when referenced to applied concentration, and passive Caco-2 permeability explained little of it.
- Correcting for measured intracellular unbound exposure shrank the spread dramatically, matching values from permeabilized cells.
Before I read a PROTAC SAR table as E3 affinity, I'd now ask what the cell actually saw. If most of the shift is unbound exposure, linker tweaks that look like potency gains may just be permeability gains, and measuring exposure early keeps us from chasing the wrong variable.
An AlphaLISA screen opens the ISG15–UBA7 interaction to inhibitor hunting
- ISG15 and its E1 enzyme UBA7 drive ISGylation, a pathway linked to treatment resistance in cancer, yet no inhibitors exist.
- The authors built an AlphaLISA assay for the ISG15–UBA7 interaction with strong robustness metrics for high-throughput use.
- A pilot screen of a small library gave a handful of hits, two of which also reduced ISGylation in cells.
This is a pilot on under a thousand compounds, so the hits are starting points, not leads. What matters is that a protein-protein interaction between a ubiquitin-like modifier and its E1 now has a screenable format. I'd run it against a real diversity set and counter-screen AlphaLISA interferers hard.
2026-10-19 2 articles
Approved anthracyclines and anthracenediones repurposed as single-molecule photosensitizers
- TD-DFT screening of a curated library of approved anticancer drugs picked out chromophore-bearing candidates with favourable photophysics.
- Mitoxantrone, pixantrone, daunorubicin and epirubicin generated reactive oxygen species on irradiation and showed enhanced cytotoxicity in breast cancer cells.
- One molecule thus supplies both the chemotherapy and the photodynamic effect, avoiding a two-component conjugate.
Starting from compounds with known PK and safety is the smart part: the CMC and tox story is already written. The catch is that these chromophores absorb at wavelengths that penetrate tissue poorly, and ROS from an anthracycline adds to cardiotoxicity worries. I'd want in vivo light-dose windows before getting excited.
Albumin-carried Fe(III) complex drives ferroptosis and immune activation in triple-negative breast cancer
- A series of Fe(III) compounds was optimized to Fe4, which was strongly cytotoxic to TNBC cells, and packaged as human serum albumin nanoparticles (HSA-Fe4).
- Structural analysis placed Fe4 in the IB subdomain of HSA, with His-146 coordinating the iron centre.
- In vivo, Fe4 and HSA-Fe4 curbed tumour growth and metastasis through Fenton-type chemodynamic therapy, ferroptosis and immune activation.
Defining the albumin binding site down to the coordinating histidine is what makes this more than a nanoparticle paper: it gives you a handle for ligand SAR. Still, a redox-active iron species hitting ferroptosis, Fenton chemistry and immunity at once is hard to deconvolve, and I'd ask for selectivity against normal tissue before reading anything into the efficacy.
2026-10-18 4 articles
3H-1,5-benzodiazepines show micromolar antimalarial activity; PfSET3 floated as target
- Eighteen new 3H-1,5-benzodiazepines were made and tested against chloroquine-sensitive and resistant P. falciparum strains, with HepG2 cytotoxicity as a first selectivity check.
- Several compounds were active in the low micromolar range, with different members showing the best potency and the best selectivity.
- The two leads were only weak inhibitors of human G9a; docking, MM-GBSA and MD were used to propose binding to parasite PfSET3.
Low-micromolar whole-cell activity with a thin selectivity window is a start, not a lead; the target claim rests on docking, which I'd treat as a hypothesis only. What I like is the unusual chemotype against a parasite epigenetic enzyme. Next I'd want a biochemical PfSET3 assay and some SAR around the best-selectivity compound.
Histone-code reading by BPTF guides a peptide–small-molecule bivalent inhibitor
- The BPTF PHD–bromodomain cassette reads H3K4me3 together with K14 acetylation, a pairing confirmed by crystallography and shown to work cooperatively, including in cis.
- The authors report first experimental evidence of a ligand-induced conformational change between the two reader domains.
- A peptide–small-molecule conjugate, MJ-1, was built from these insights and inhibits both domains, addressing the usual ligandability problem of PHD fingers.
Everyone has chased BPTF bromodomain binders with limited payoff; the PHD finger is the hard half, and a bivalent design is a pragmatic way to borrow affinity from a peptide. The catch is that a peptide conjugate is far from a cell-permeable lead. I'd want to see which half carries the potency and whether a fully small-molecule version holds up.
De novo designed proteins bind MYC's disordered regions and slow MYC-driven tumors
- Designed proteins target conserved epitopes in MYC, including intrinsically disordered motifs needed for its oncogenic activity.
- They bind MYC tightly in vitro; in cells they engage MYC, disrupt MAX pairing and reshape MYC-associated complexes.
- Expressing the binders curbed proliferation across several MYC-dependent hematopoietic, liver, pancreatic and patient-derived models, and depleted tumor cells in an orthotopic pancreatic model.
MYC has no pocket for a small molecule to sit in, so going after disordered epitopes with designed binders is a sensible way around that. For us it's a target-validation tool first: expression inside the cell says nothing about delivery, and a protein binder won't become a drug without a delivery story. Still, it shows where a small-molecule PPI or degrader program should aim.
mRNA-display macrocycle IMP2660 gives the first effector-free RAB27A structure
- mRNA display against the RAB27A effector-binding interface produced macrocyclic peptide hits, which were optimized into IMP2660.
- IMP2660 binds RAB27A tightly and disrupts RAB27A–effector interactions.
- Its co-crystal structure with active-state RAB27A, solved without any effector, maps the effector-binding surface for structure-guided design.
The crystallography chaperone angle is the underrated payoff: wild-type RAB27A only crystallized with its effector, so a clean macrocycle-bound structure unlocks soak-in and fragment work. Whether IMP2660 itself is more than a tool is another matter, since permeability for a nonapeptide-sized macrocycle against an intracellular GTPase is the obvious hurdle.
A potent macrocyclic peptide binder enables effector-free crystallization of the GTPase RAB27A ↗
2026-10-17 6 articles
Incyte's oral MRGPRX2 antagonist INCB187175 emerges from scaffold hybridization
- MRGPRX2 drives IgE-independent mast cell activation and is linked to urticaria, atopic dermatitis and pseudoallergic reactions.
- Scaffold hybridization and SAR gave pyrazolopyrimidine antagonists active in both Gq/IP1 and β-arrestin assays.
- Fixing solubility and CYP inhibition liabilities led to INCB187175, orally exposed across species, which blocked degranulation in primary human mast cells and mast cell activation in vivo.
Scoring on both Gq and β-arrestin readouts is the right call for a receptor where bias could muddy the pharmacology. The solubility and CYP fixes read like a practical optimization story, not a lucky hit. The crowded MRGPRX2 field means the real differentiator will be human exposure and how well mouse-proxy assays translate for a human-restricted receptor.
Discovery of Pyrazolopyrimidines as Potent and Orally Bioavailable MRGPRX2 Antagonists ↗
Molecular dynamics finds a RhoJ-specific N-terminal pocket, and terconazole disrupts PAK3 binding
- RhoJ is nearly identical to Cdc42 in sequence but carries a unique N-terminal extension, which simulations show forms an allosteric pocket on binding PAK3.
- Structure-based virtual screening against that pocket flagged the antifungal terconazole as a possible binder.
- In live cells, an optimized BRET2 biosensor showed terconazole reduces the RhoJ–PAK3 interaction in a dose-dependent way.
Using a sequence extension absent from Cdc42 to buy selectivity is exactly how I'd attack a conserved GTPase. But terconazole is a repurposed azole with modest credentials as a starting point, and a BRET drop alone can't prove pocket engagement. I'd want mutagenesis of the N-terminal residues and a biophysical binding readout before calling this validated.
Identification and targeting of a novel drug pocket in the tumour angiogenesis regulator RhoJ ↗
Crystal structures show how CNS-oriented EGFR TKIs gain potency, not just brain exposure
- Several EGFR TKIs redesigned for blood-brain barrier penetration were studied by X-ray crystallography and potency assays.
- The BBB-enhancing groups engage varied regions of the EGFR kinase domains, and biochemical and cellular potency generally improved.
- Salt-bridge-forming moieties combined with certain halogen substitutions worked best, pointing to a 'two-for-one' design logic.
CNS exposure and potency are usually traded off against each other, so a crystallographic case that the same polar or basic handle can buy both is useful. The salt-bridge-plus-halogen pairing is a concrete design rule I could try on my own kinase series. It does not address efflux or unbound brain concentrations, which still decide whether it works in a patient.
Structural Insights into Brain-Penetrant EGFR Tyrosine Kinase Inhibitors with Enhanced Potency ↗
A covalent ligand at cereblon's cryptic Cys287 locks the E3 ligase open and blocks IMiD-driven degradation
- Cysteine-directed chemoproteomic screening found covalent ligands for Cys287, an allosteric pocket far from the thalidomide-binding site.
- Lead VVD-105917 broadly blocks degradation of neosubstrates driven by IMiDs and CELMoDs.
- Cryo-EM shows it traps cereblon in its open, inactive state, and ligand order matters. A previously reported ligand at the same site promotes closure instead, so the pocket is 'sign-switchable'.
Every CRBN drug so far sits in one orthosteric pocket, so a covalent handle that controls the open/closed switch is a genuinely new knob. A pan-inhibitor is an excellent tool to dissect degrader mechanisms and rescue off-target degradation. A site that can push either way also means a degrader-enhancing ligand might be hiding in the same pocket. This is a preprint, so wait for review.
Allosteric covalent inhibition of cereblon through cryptic cysteine targeting ↗
Adamantane-capped indole hydroxamate YP200 pushes HDAC11 selectivity into a lung cancer PDX model
- Starting from the earlier lead PB94, the authors optimized the core, linker and cap of an indole-based hydroxamic acid series against HDAC11.
- The best compound, YP200, combines a secondary-amine linker with an adamantane surface-recognition cap.
- It showed high potency for HDAC11 with strong selectivity over other HDAC isoforms, and suppressed tumor growth in a patient-derived NSCLC xenograft.
Hydroxamates are rarely clean across isoforms, so a bulky adamantane cap doing the selectivity work is the part I'd chase: it suggests HDAC11's narrow channel rewards cap size more than zinc-binder tweaks. Given the recent probe-validity debate around HDAC11 tools, I'd want kinetic isoform panels and cellular target engagement before trusting the efficacy story.
A 5-azaindole TTBK1/2 probe with a matched negative control disrupts ciliogenesis
- The 5-azaindole inhibitor 13 is potent against tau tubulin kinases 1 and 2 and active in cells.
- In-cell kinome profiling showed few off-targets; follow-up NanoBRET work narrowed them to CDK11A/B, CK1δ and PIKfyve.
- A close analogue, compound 5, lacks in-cell TTBK affinity and serves as a negative control; compound 13 blocks TTBK2 autophosphorylation and impairs primary cilia formation in RPE-1 cells.
What I like here is the discipline: a kinome-wide in-cell selectivity map, honest naming of the CDK11 and PIKfyve liabilities, and a matched inactive control. That is what a probe should look like before anyone reads biology into a ciliogenesis phenotype. The CDK11 overlap is the caveat I'd test first, with an orthogonal chemotype.
Potent and Cell Active 5-Azaindole-based Tau Tubulin Kinase Inhibitors Disrupt Ciliogenesis ↗
2026-10-16 8 articles
High-content screen of a covalent library finds new early mitotic inhibitors
- A cell-based high-content imaging screen was built to catch early mitotic spindle assembly defects.
- Run against a 3,520-compound cysteine-reactive library, it found a microtubule depolymerizer, a spindle-positioning disruptor and compounds that disturb spindle structure and chromosome alignment.
- Two hits caused mitotic arrest and reduced cancer cell viability (preprint; not yet peer reviewed).
Phenotypic screening with a covalent library is a sensible way to find chemotypes that target-based approaches would never pick. The weak point is deconvolution: until the cysteine targets are identified, a microtubule depolymerizer risks being one more tubulin binder. Worth tracking for the non-tubulin hits.
Identification of Cysteine-Reactive Early Mitotic Inhibitors ↗
Elevenostat is a multi-HDAC inhibitor biased to HDAC6, not an HDAC11-selective probe
- Re-testing Elevenostat (JB3-22) against recombinant HDAC isoforms with two orthogonal HDAC11 assays showed only weak HDAC11 inhibition.
- Full HDAC1–11 profiling found much stronger inhibition of HDAC6 and HDAC10, plus class I enzymes, with HDAC11 the least sensitive isoform.
- Cellular readouts (tubulin and histone acetylation, reduced viability) matched HDAC6 and class I engagement, so past HDAC11 conclusions drawn from this compound need re-reading.
This is the unglamorous but valuable kind of paper: a compound used as an HDAC11 tool turns out to hit HDAC6 hardest. Any phenotype published with Elevenostat now has an attribution problem. Before I reuse an inhibitor as a probe, I want full-panel selectivity and a matched inactive control, which this case argues for.
Aminopyrimidine NaV1.7 probe inhibits resting and inactivated states almost equally
- An automated patch-clamp screening cascade, built to deprioritize classic local-anesthetic pore binders, yielded an aminopyrimidine hit that was optimized into compound 6.
- Compound 6 combined balanced resting- and inactivated-state potency, selectivity over NaV1.5 and a tetrodotoxin-like isoform profile that includes NaV1.1.
- SAR pointed to the aminopyrimidine core and a methylene-linked aniline as key determinants of this profile.
State dependence is a leading suspect for why NaV1.7 programs keep failing clinically, so a probe that blocks resting and inactivated states alike is a good way to test that hypothesis. NaV1.1 activity is a flag for seizure-related liability, and I'd want a binding-site assignment before reading too much into the profile.
A Nontoxin Aminopyrimidine Probe for Near State-Independent Na V 1.7 Inhibition ↗
Turning EGFR kinase inhibitors into BAX inhibitors with the kinase activity engineered out
- A virtual screen flagged EGFR inhibitors, including dacomitinib and gefitinib-like cores, as possible BAX binders.
- Systematic modification built a first SAR for BAX inhibition and reduced EGFR kinase activity considerably.
- The series showed better BAX inhibition in vitro, in cells and in iPSC-derived brain organoids, with drug-like properties.
Inhibiting an executioner protein like BAX is hard, so starting from a privileged kinase scaffold is pragmatic. The real test is whether the EGFR activity is gone enough: a cytoprotectant that still hits kinases is a poor neuroprotective. I'd like orthogonal proof of direct BAX engagement and a broader kinome panel.
Scaffold-hopped BCL6 PROTAC degrades its target in DLBCL cells and works orally in xenografts
- Scaffold hopping from the BCL6 ligand BI-3802 gave a new tricyclic oxazinoquinolinone binder.
- Linker and CRBN-recruiter tuning produced compound 15, a PROTAC that degraded BCL6 quickly and potently, in a CRBN- and proteasome-dependent way.
- It strongly suppressed BCL6-dependent DLBCL cell growth, and oral dosing inhibited tumor growth in an OCI-LY1 xenograft without evident toxicity.
BI-3802 is a polymerizing degrader with a peculiar mechanism, so a conventional CRBN-recruiting PROTAC from a fresh tricyclic core is a useful alternative route to BCL6 removal. Oral efficacy matters most here; I'd want to see how the molecule balances size and permeability, and whether degradation depth tracks with tumor response across non-OCI-LY1 lines.
GTA182: a brain-penetrant MTA-cooperative PRMT5 inhibitor for MTAP-deleted tumors
- Structure-based design and multiparameter optimization gave GTA182, a tricyclic amide with strong selectivity for MTAP-deleted over wild-type cells.
- Low efflux and tuned physicochemical properties delivered unbound brain exposure in the efficacious range.
- Orally dosed, it caused regression in MTAP-deleted xenografts and an orthotopic glioblastoma model, and early Phase I data reported good tolerability and intracranial tumor shrinkage.
MTA-cooperative PRMT5 inhibitors are crowded, and brain exposure is the clear differentiator: MTAP deletion is common in glioblastoma, where most competitors can't reach the tumor. A clinical readout appearing in a medicinal chemistry paper is rare. I'd now look at hematologic safety, the usual liability for this class, and at how much of the intracranial effect is truly unbound-drug driven.
Cryo-EM-guided pocket merging yields an oral allosteric SLC6A19 inhibitor
- Virtual screening against the allosteric pocket seen in the SLC6A19/cinromide cryo-EM structure gave a starting hit.
- A second, partially overlapping pocket from a further cryo-EM structure inspired merged analogues, leading to a potent, selective, orally bioavailable compound 20.
- Compound 20 was weaker on mouse than on non-human primate SLC6A19, yet oral dosing raised urinary amino acid excretion dose-dependently.
Membrane transporters rarely give such a clean example of structure-driven design: two cryo-EM pockets, one merged series, in vivo pharmacodynamics from a simple urinary readout. The mouse potency shift is the practical snag for efficacy models, so the primate retention is reassuring. Next I'd want to know the margin for amino acid depletion.
HTS framework finds small molecules that block tau binding to the LRP1 receptor
- The team built a quantitative assay set around purified LRP1 ligand-binding domain 4, using fluorescence polarization, split luciferase and TR-FRET.
- Tau, RAP and a peptide ligand competed for overlapping binding sites with nanomolar-range affinities across formats.
- A screen on this platform identified small-molecule inhibitors of the interaction, a starting point against tau uptake and spread.
Protein–protein interactions with a receptor ectodomain are tough targets, so three orthogonal assays is the right way to weed out artifacts. I'd treat the hits cautiously until they show activity in cellular tau-uptake assays and clear LRP1's many other ligands, such as ApoE and RAP, without broad liabilities.
High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction ↗
2026-10-15 6 articles
mRNA-display macrocycles reveal CHD4 as an interaction hub in the NuRD complex
- mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex.
- The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined.
- Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.
One selection campaign delivering both hits and biology is a nice outcome. Macrocycles sitting on a protein–protein interface are rarely drug-like as they stand, so my question is whether the ternary structure lets us shrink them toward something cell-permeable; the second site on CHD4 gives another handle for that. I'd also want to see selectivity against related remodelers.
Cinchona-derived ammonium salts give long-lasting, sensory-selective nerve block
- Ammonium salts built on natural cinchona alkaloids were explored as local anesthetics; the bicyclic quincoridine skeleton beat acyclic and monocyclic analogues.
- Lead CLA-1-3 blocked the rat sciatic nerve for more than 50 hours and potently inhibited voltage-gated sodium channels.
- A second compound, CLA-3-5, gave a sensory-selective block lasting up to about 3 hours at 0.30–0.60% concentration.
Duration is the headline, but the permanently charged ammonium is the more interesting design choice: it should slow washout from the injection site, which probably explains the long action. For anything that lasts over 50 hours, though, I'd look at local neurotoxicity and myotoxicity data before the efficacy curves.
Cinchona Alkaloids-Derived Ammonium Salts for Long-Acting and Sensory-Selective Nerve Blockades ↗
Bicyclic amine swap widens the G2019S window in indazole LRRK2 inhibitors
- Structure-guided hybridization produced an indazole-based LRRK2 series; the initial piperidine compounds were potent but barely distinguished wild-type from G2019S mutant kinase.
- Replacing the piperidine with an octahydrocyclopenta[c]pyrrole widened the selectivity window while keeping good potency; compound 34 represents the new chemotype.
- The authors pitch it as an alternative starting point for next-generation, Parkinson's-directed LRRK2 inhibitors.
Locking a floppy piperidine into a fused bicycle is the textbook way to sharpen selectivity, and it seems to have paid off here. Before getting attached I'd check what the extra carbon framework costs in lipophilicity and brain exposure, because a CNS target punishes both. Mutant-over-wild-type selectivity also needs to hold up in cells, not just in biochemical assays.
Oral non-peptide STAT6 degrader WW-210 eases atopic dermatitis in mice
- Replaces the earlier phosphopeptide-based STAT6 PROTAC with non-peptide degraders designed for oral dosing.
- WW-210 degraded STAT6 at very low concentrations with a wide selectivity window over other STAT family members.
- It showed measurable oral bioavailability and degraded STAT6 in blood and spleen; in an atopic dermatitis mouse model it eased skin lesions, lowered serum IgE and reduced mast cell infiltration.
STAT6 is a transcription factor with a flat, polar SH2 surface, exactly the kind of target where inhibitors struggle and degraders can sidestep the problem. Getting oral exposure from a PROTAC that started life as a phosphopeptide is the real achievement; I'd like to see how molecular weight and polarity were managed, and whether the STAT-family selectivity holds in primary T cells.
HTS-derived covalent inhibitors hit active, GTP-bound KRAS G12C
- Approved KRAS G12C drugs mostly trap the inactive GDP state and face resistance; this series targets the active GTP-bound state instead.
- A keto-indolizine HTS hit with an aniline-derived acrylamide binds Cys12 in the switch-II pocket; crystallography shows the warhead engaging the γ-phosphate of a GTP analogue.
- Optimization gave compound 17, orally bioavailable in preclinical species, which prolongs disruption of KRAS–cRAF binding and ERK signalling and produced complete regression in a pancreatic cancer xenograft.
Using the γ-phosphate to position the warhead is neat: GTP-state selectivity comes from the nucleotide itself, not only the pocket. The comparison I'd want is against RAS(ON) tri-complex inhibitors, which need cyclophilin A while this doesn't. Acrylamide reactivity and proteome-wide cysteine selectivity also matter more here than for GDP-state binders.
Covalent fragments reach lysines in the SHP2 allosteric latch site
- Combines an electrophile-first covalent fragment screen with a ligand-first strategy to target lysines in the allosteric latch site of SHP2 phosphatase.
- Computational and experimental analyses support the binding mode, and the work yields what the authors call the first potent, cell-active allosteric covalent inhibitors at this site.
- It shows the latch site is covalently tractable, opening routes to new allosteric SHP2 chemotypes.
Lysine-directed covalent chemistry is far rarer than cysteine, so a workflow that actually delivers cell-active hits on a lysine is the takeaway, more than SHP2 itself. My caveat is reactivity versus stability: lysine electrophiles can be hydrolytically fragile or reversible, so I'd want proteome-wide selectivity data before calling anything a probe.
Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗
2026-10-14 8 articles
Optimised benzothiophenes block Mtb virulence by inhibiting the MprB histidine kinase
- The earlier hit BTP15 protects host cells from Mtb-induced death by blocking phagosomal escape through MprB inhibition, but had poor pharmacokinetics.
- New benzothiophene analogues were screened for MprB inhibition, microsomal stability, toxicity and ex vivo efficacy in THP-1 and MRC-5 cells.
- The aim is a virulence-blocking route that avoids killing the bacterium directly, which may reduce resistance pressure.
Antivirulence is attractive on paper, but the hard part is demonstrating efficacy without a bactericidal readout. I'd look hardest at whether the stability gains translate into in vivo exposure, since BTP15's problem was PK, and at whether MprB engagement is shown cleanly in the infected-cell setting.
Turning eltrombopag into DCL1191, an oral inhibitor of the 'undruggable' TFEB
- TFEB, a transcription factor long seen as undruggable, was approached starting from eltrombopag, which has weak TFEB inhibitory activity alongside its Tpo-R agonism.
- SAR optimisation gave DCL1191, which binds TFEB, disrupts TFEB–DNA binding and shows reduced Tpo-R and MITF activity; modelling and mutagenesis support the binding mode.
- It represses TFEB target genes, blocks autophagic flux and is orally bioavailable, with activity in autophagy-hyperactivated glioblastoma cells.
Starting from a marketed drug with a known off-target is a smart way into a transcription factor, because you inherit drug-like properties. The real test is the MITF/TFE3 family: if selectivity over close paralogues holds, this is a genuine tool compound rather than another autophagy-flavoured cytotoxin.
Co-crystal-guided HDAC6 inhibitors that reach the L2 loop and trigger autophagy in lung cancer cells
- Second-generation HDAC6 inhibitors were designed from X-ray structures of earlier compounds bound to the zebrafish HDAC6 catalytic domain.
- Co-crystal structures of two leads showed engagement of S531 in the L2 loop; cells showed raised acetylated tubulin without a clear histone acetylation change.
- One lead cut A549 viability in 2D and 3D culture through pro-autophagic signalling and also affected phase-separation behaviour.
Grabbing the L2 loop is the obvious handle for isoform selectivity: the CD2 pocket is conserved, the loop is not. Acetylated tubulin up and histones flat is the readout I want before believing a selectivity claim. I'd still ask for a broad HDAC panel and some PK before getting excited about the autophagy story.
PDIA3 inhibitors from an N-hydroxyindole series act as host-targeted antivirals against respiratory viruses
- PDIA3, an ER oxidoreductase involved in folding glycosylated viral envelope proteins, is an underexplored host target for antivirals.
- A new N-hydroxyindole-2-carboxamide class, exemplified by AV22, inhibits PDIA3 and shows broad activity against major human respiratory viruses.
- In coronavirus-infected cells AV22 raised release of non-infectious particles and reduced disulfide bond formation in spike.
Host-directed antivirals dodge resistance but live or die on the therapeutic window, because PDIA3 does real work in uninfected cells. An N-hydroxy group is also a flag for me: metal binding and metabolic liability can both bite. I'd look first at cytotoxicity margins and microsomal stability.
In silico building-block selection widens the diversity of a 403,200-member peptide-like DEL
- A three-cycle, peptide-like DEL of 403,200 compounds was built, with a chemical space model of 4,774 commercial amino acids used to find under-represented building blocks.
- Affinity selections were run against three targets to compare library performance.
- Selection against carbonic anhydrase II recovered the known sulfonamide pharmacophore, supporting the computational design approach.
Recovering the sulfonamide on CA II is the expected sanity check, not proof of lead-like coverage. Peptide-like DELs often return big, polar hits, so what I'd judge is how many selected compounds sit in usable property space off-DNA, and how the two other targets behaved.
First thiazolamide PI4KIIIβ/HDAC dual inhibitors take a host-directed route against HCV
- Host-directed dual inhibition of PI4KIIIβ and HDACs had not previously been reported for hepatitis C, where resistance to direct-acting antivirals remains a concern.
- A series of thiazolamide-based dual inhibitors was designed, synthesised and evaluated.
- Lead compounds showed potent enzymatic inhibition of both targets together with anti-HCV activity.
With DAAs curing most patients, the case for a host-directed HCV drug is hard to make commercially, and a dual PI4KIIIβ/HDAC profile adds tox risk. I read this as a good exercise in multitarget design, but would want to see cytotoxicity and kinase selectivity before calling the window real.
Oral STING inhibitor D4 protects against severe acute pancreatitis in mice
- SAR work identified D4, which binds STING directly and blocks its oligomerization and downstream TBK1/IRF3 signalling.
- In macrophages it restored phagocytosis, autophagic flux and mitochondrial function while dampening NLRP3-linked pyroptosis.
- D4 was orally exposed and well tolerated at high dose, and cut pancreatic injury and enzyme levels in a caerulein/LPS model; STING knockdown looked similar.
Most STING programs chase agonists for oncology; an orally available inhibitor for an acute inflammatory indication is a different bet. The knockdown phenocopy is reassuring on mechanism, but I'd want to know how it behaves across species, since STING ligand pockets are notoriously species-dependent, and whether an acute dosing window is realistic in patients.
Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis ↗
Millepachine hybrid hits tubulin and HDAC8 together in ovarian cancer models
- The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
- Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
- It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.
HDAC8 is a less crowded choice than the usual HDAC6/class I pairing, and pairing it with a tubulin binder is mechanistically coherent. My worry is the classic one for dual hybrids: the two activities rarely scale together, so I'd want evidence that HDAC8 inhibition, not just the tubulin arm, contributes to the in vivo effect.
2026-10-13 5 articles
Longer semi-rigid linkers drive VHL-based HDAC6 degraders with antileukemic activity
- A solid-phase route enabled systematic variation of VHL ligand, exit vector and linker in vorinostat-derived HDAC6 PROTACs.
- Longer, semi-rigid linkers gave the best degradation; the lead compounds degraded HDAC6 preferentially in MM.1S and MV4-11 cells.
- A matched non-degrading control with similar HDAC inhibition was clearly less antiproliferative, pointing to degradation itself as the driver.
The non-degrading control with matched enzyme inhibition is the kind of experiment that separates degradation from plain inhibition, and it favors the PROTAC. Preferential, not exclusive, HDAC6 selectivity from a vorinostat-like warhead is the weak point; a more isoform-selective ligand might sharpen it.
Ferulic acid-based PROTAC degrades TLR4 to protect endothelial cells
- Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
- The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
- Protection was also seen in zebrafish, extending PROTAC use beyond oncology.
Using a PROTAC to rescue a weak natural-product binder is clever, but TLR4 is a membrane receptor and the evidence here is thin on which E3 ligase is engaged and on ternary-complex dependence. I'd ask for rescue experiments with ligase and proteasome inhibitors before believing the mechanism.
Fully G protein-biased GPR183 agonist TUG-2604 reaches oxysterol-like efficacy
- SAR optimization of earlier virtual-screening hits, themselves derived from the antagonist NIBR189, gave full GPR183 agonists with complete G protein bias.
- The lead, TUG-2604, matches the endogenous oxysterol 7α,25-OHC in potency and efficacy without recruiting β-arrestin2.
- It failed to drive human dendritic cell migration on its own and blocked migration induced by the oxysterol.
Turning an antagonist-derived hit into a full agonist with complete G protein bias is not routine, and the migration data hint that β-arrestin signaling carries the chemotaxis. For anyone weighing GPR183 in inflammation, this is a clean tool to separate the two arms before committing to a direction.
Development of Potent G Protein Pathway-Biased GPR183 Agonists ↗
Scaffold-hopping screen yields a 2-OG-noncompetitive KDM6B inhibitor active in cervical cancer xenografts
- Scaffold-hopping virtual screening produced a diaryl pyrimidine-guanidine series against the JmjC demethylase KDM6B, which is overexpressed in cervical cancer.
- The optimized lead matched GSK-J4 in enzyme potency but is non-competitive with 2-oxoglutarate, a different binding logic from most JmjC inhibitors.
- Despite pan-KDM activity in vitro, it selectively raised H3K27me3 in C33A cells and slowed xenograft growth.
Most JmjC inhibitors live or die on 2-OG-site chemistry and its polarity baggage, so a non-competitive series is a genuinely different starting point. I'd want to know why enzyme-level pan-KDM activity collapses to H3K27me3 selectivity in cells, and what the guanidine does to permeability.
Fixing solubility and CLK4 off-target liability in STK33 male-contraceptive indazoles
- SAR and property work on the 3-(biphenylethynyl)-1H-indazole scaffold behind CDD-2807 targeted its poor kinetic solubility.
- CDD-3094 kept nanomolar cellular potency while gaining solubility, lowering hERG liability and showing a clean broad kinase panel.
- A co-crystal structure guided changes against the main off-target CLK4, giving a strongly selective biochemical tool whose cellular potency dropped.
This is a textbook potency-versus-properties trade: solubility fixed in CDD-3094, then selectivity bought at the price of cell activity. For a contraceptive, where the safety bar is far higher than in oncology, the CLK4 discrimination matters more than raw potency; the next step is recovering permeability.
2026-10-12 6 articles
Donepezil-derived dual BuChE/FAAH inhibitors for multi-target Alzheimer's therapy
- Donepezil-based derivatives were designed and made as dual inhibitors of human butyrylcholinesterase and fatty acid amide hydrolase.
- Lead G15 inhibited both enzymes in a balanced way, with sub-micromolar to low-micromolar activity.
- It showed measurable selectivity over the carboxylesterases CES1 and CES2, a common liability for serine-hydrolase inhibitors.
Dual-target hybrids rarely land balanced potency on both enzymes, so G15 is a useful starting point. Selectivity over carboxylesterases is only modest, though, and I'd want in vivo exposure data before believing the multi-target rationale.
Hybrid indazole–bicyclic pyrrole chemotype targets mutant-selective LRRK2
- Structure-guided hybridization of an indazole with an octahydrocyclopenta[c]pyrrole gave a new LRRK2 inhibitor chemotype for Parkinson's disease.
- Early piperidine-containing analogs were potent but barely distinguished wild-type from G2019S LRRK2.
- Swapping the piperidine for the fused bicyclic amine was the change introduced to widen that selectivity window.
A narrow wild-type/G2019S window is the usual reason LRRK2 leads stall, so a scaffold change that buys mutant bias is worth a look. I'd want to see whether that bias holds in cells at physiological ATP and what the bicyclic amine does to brain penetration and clearance.
Bis-catecholate siderophore carries ampicillin into resistant Pseudomonas
- A Trojan-horse design hijacks bacterial iron uptake to move a β-lactam payload across the Gram-negative outer membrane.
- Ampicillin was conjugated to mono-catecholate, bis-catecholate and catecholate–hydroxamate siderophores and the series compared.
- The bis-catecholate conjugate is reported as the selective one, extending ampicillin's reach to multidrug-resistant P. aeruginosa.
Getting an old penicillin to work on Pseudomonas by changing only the delivery vector is a clean demonstration of the siderophore approach. Linker stability in serum and the chance that resistant strains simply down-regulate the uptake receptors are the things I'd check next.
Lactam bridge replaces oxidation-prone thioether in an IL-11 antagonist peptide
- The oxidation-sensitive thioether in an IL-11-binding peptide was replaced with a lactam bridge, with linker length screened systematically.
- The optimized analog 4L6–16 bound IL-11 with good affinity and antagonized it more strongly than the starting peptide.
- It showed renoprotective effects in both cell and animal models of renal fibrosis.
Swapping a thioether for a lactam is a textbook peptide-stability fix, and it's encouraging that it also improved antagonism rather than just shelf life. Binding in the mid-nanomolar range leaves room to tighten, and proteolytic stability in plasma is the next number I'd ask for.
Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment ↗
Kinetic target-guided synthesis yields potent hydroxamate LasB inhibitors
- Guided by earlier crystal structures, kinetic target-guided synthesis was used to assemble inhibitors of the P. aeruginosa virulence factor elastase LasB.
- Extensive SAR gave hydroxamic acid inhibitors with very high potency and good selectivity over a panel of human off-targets.
- The compounds protected lung epithelial cells from LasB damage, showed in vivo efficacy, and reached lung exposure above their biochemical potency.
Using the enzyme itself to pick its best fragment pairs is a smart way into a metalloprotease pocket, and the lung PK above IC50 is exactly the data antivirulence programs usually lack. Hydroxamates still carry metabolic and zinc-binding baggage, so the off-target panel on other metalloenzymes is where I'd look first.
Masking a bisphosphonate makes acid sphingomyelinase inhibitors cell-active
- The charged amino bisphosphonate inhibitor ARC39 of acid sphingomyelinase was masked to improve cell entry.
- Masked derivatives reached nanomolar activity in cells, about two orders of magnitude better than the parent.
- Cell uptake, stability and related properties were characterized in detail.
Phosphonate masking is a familiar trick, but ASM has lacked a potent cell-active tool, so a hundred-fold gain in cells matters for target validation. Whether the masks unveil cleanly in the lysosome, where ASM works, decides if this is a probe or a lead.
Masked Bisphosphonate Inhibitors of Acid Sphingomyelinase: Improved Cell Penetration and Potency ↗
2026-10-10 7 articles
Brain-penetrant colchicine-site tubulin ligand nominated for glioma
- Only temozolomide and vorasidenib are approved brain-permeable, orally available drugs for brain cancers, so the team sought new brain-penetrant options.
- SAR work yielded a new class of highly brain-penetrant tubulin ligands; co-crystal structures confirm colchicine-site binding, with the tubulin βT7 and αT5 loops flipped relative to the colchicine-bound state.
- SAR showed high sensitivity to substitution with few indispensable moieties, leading to compound 40 as the clinical candidate.
Tubulin binders that actually cross the blood-brain barrier usually die on P-gp efflux or neurotoxicity, so a tight series with strong brain exposure is notable. The flipped βT7/αT5 loops hint at a binding mode worth docking my own colchicine-site scaffolds against. Chronic neurotoxicity is still the question.
DNMT1 PROTAC B7 blocks catalytic and scaffolding roles in liver fibrosis
- DNMT1 drives fibrogenesis through both catalytic and non-catalytic mechanisms, so the team built PROTAC degraders starting from DC-517 to hit both at once.
- Lead compound B7 mediates ubiquitin-proteasome degradation of DNMT1, lowers global DNA methylation and suppresses profibrotic responses in vitro.
- In vivo, B7 reduced DNMT1 levels and attenuated liver fibrosis, with less collagen deposition and better hepatic function.
DNMT1 is a textbook case for degrading rather than inhibiting, because an active-site inhibitor leaves the scaffolding role untouched. My worry is selectivity for liver and what removing an essential maintenance methyltransferase does in dividing tissue; fibrosis models are forgiving on both counts.
Boronic acid ENPP1 inhibitors stay active across tumor-relevant pH
- ENPP1 hydrolyzes cGAMP in the tumor microenvironment and so dampens STING-driven antitumor immunity.
- Inspired by the phosphate-based inhibitor STF-1084, the team made non-nucleotide inhibitors with a boronic acid zinc-binding group, leading to compound 36, which stays potent across pH.
- Compound 36 boosted cGAMP-mediated STING activation in vitro and gave tumor growth inhibition as monotherapy in a syngeneic CT26 model, with a synergistic effect alongside oxaliplatin and no observed toxicity.
Phosphate- and phosphonate-type ENPP1 binders have always struggled with permeability and exposure, so swapping in a boronic acid zinc binder is a cleaner route. Designing for acidic-pH activity is the smart part, since that is where the enzyme works. Single-agent efficacy by IP dosing is modest, so oral exposure and boronic acid stability are my next questions.
Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy ↗
Binding kinetics help isolate HDAC2-selective inhibitor KTT-1
- KTT-1 (compound 12) was identified as HDAC2-selective by evaluating both thermodynamics and kinetics of enzyme–inhibitor binding, rather than affinity alone.
- Crystallography of HDAC2 with the compound, plus quantum chemical calculations on model compounds, suggests its 2-furanyl group drives the selectivity.
- In cells it preferentially inhibited HDAC2 over the highly homologous HDAC1 and promoted neurite outgrowth; in stress-vulnerable mice it improved memory and depression-like behavior.
Screening on residence time rather than IC50 alone is how you get past the near-identical HDAC1/2 active sites, and a furanyl contact backed by both crystallography and QM is a clean, testable rationale. Cellular HDAC2-over-HDAC1 preference is rare, so I'd want it confirmed in neurons with real brain exposure.
Chimeric Hsp90β-selective inhibitors keep selectivity while tuning PK
- Pan-Hsp90 inhibitors stalled clinically because of their broad inhibition, so Hsp90β-selective indazolone compounds have been pursued, though earlier ones needed long optimization to become drug-like.
- This work modifies the northern indazolone fragment and the southwestern appendage at the same time, testing whether the best traits of each region can be combined.
- The resulting chimeric inhibitors retain Hsp90β affinity and selectivity while shifting key pharmacokinetic parameters.
Merging two independently optimized vectors is a sensible, low-risk move, and selectivity surviving the merge suggests the β-specific pocket tolerates more change than I feared. What would decide it for me is tissue exposure and tolerability, since that is where pan-inhibitors failed.
DEL hit becomes brain-penetrant reversible MAGL inhibitor MAGLi 432
- A bicyclopiperazine hit from a DNA-encoded library was optimized by structure-guided design into compound 1.5 (MAGLi 432), a reversible MAGL inhibitor.
- The compound combines high potency, selectivity over other serine hydrolases and CNS drug-like properties, with a favorable oral half-life in rats.
- It inhibited MAGL in human brain homogenate and worked in mouse neuroinflammation models; the campaign was steered by a translational "Five-Star Matrix" framework.
Reversibility is the part I'd want here, since irreversible MAGL agents ran into CB1 desensitization on chronic dosing. A non-covalent DEL chemotype that already shows target engagement in human brain tissue is a good template, and I'd steal the habit of testing in human tissue early rather than at the end.
Screening under 0.1% of a library yields new QPCT/L inhibitor tool BI-3614
- QPCT and Golgi-bound QPCTL convert N-terminal glutamines to pyroglutamate, affecting Aβ oligomerization, chemokine stability and CD47–SIRPα signaling.
- A virtual screen selecting under 0.1% of an in-house library, based on similarity to bioactive conformations of known inhibitors, delivered new chemotypes and sped up hit discovery.
- Structure-guided optimization of a quinazolidinone series gave the cellular tool compound BI-3614, with improved activity over earlier inhibitors.
Screening under a tenth of a percent and still finding fresh chemotypes is the efficiency argument for conformation-based similarity searching. The old QPCT inhibitors leaned on metal-binding groups, so a new cell-active series is welcome for CD47 pyroglutamate biology. QPCT versus QPCTL selectivity is what I'd check first.
2026-10-09 6 articles
Pose prediction plateaus after about five crystal structures per scaffold
- Using 403 SARS-CoV-2 main protease structures from the open COVID Moonshot campaign, the authors asked how many new crystal structures are worth collecting.
- Similar reference ligands give the best pose prediction, and success plateaus at roughly five structures per Bemis-Murcko scaffold, exceeding 95% for the lead series.
This gives structural biology a concrete budget line: after about five structures per scaffold, the next soak buys little for pose prediction. Caveat: Mpro is a rigid, well-behaved pocket, so I'd not carry that number over to flexible kinases or induced-fit targets.
How Many Crystal Structures Do You Need to Trust Your Docking Results? ↗
Property-driven design yields inhaled sGC stimulator frespaciguat for PH-COPD
- Oral sGC stimulators can cause systemic hypotension and worsen ventilation-perfusion mismatch in PH-COPD, motivating a lung-restricted design.
- SAR and PK work identified high systemic clearance and low permeability as the key drivers of pulmonary selectivity.
- Compound 15 (frespaciguat, MK-5475) is a very potent stimulator with long target residence time and more than 200-fold unbound lung-to-plasma exposure after inhalation, with efficacy in a rat chronic hypoxia model.
Designing for high clearance and low permeability on purpose is the opposite of oral-drug instinct, which is exactly why this paper is useful for inhaled programs. Residence time plus lung retention is the combination I'd want to see replicated before believing the therapeutic window in humans.
Lipophilicity-controlled optimization delivers PERK inhibitor APL-11056
- Starting from a literature-derived PERK inhibitor of moderate potency but good kinase selectivity and PK, the team ran a lead optimization campaign steered by log D and lipophilic ligand efficiency.
- This produced APL-11056 (compound 49), a potent and selective PERK inhibitor with excellent in vivo pharmacokinetics.
- High permeability is linked to a fluorine alpha to the core benzamide, which appears to limit efflux-transporter recognition.
Letting LLE drive the SAR instead of chasing potency is the discipline that makes this readable, and the alpha-fluoro benzamide trick for dodging efflux is a handy one for my own amide series. PERK's ISR biology has bitten inhibitors before, so the tolerability data will matter more than the PK table.
Oral POLQ polymerase inhibitors regress BRCA2-null tumors with olaparib
- POLQ drives microhomology-mediated end joining, making it a synthetic-lethal target in homologous-recombination-deficient cancers.
- Optimizing a weak biochemical hit gave benzimidazole/purine inhibitors; compound 37 is potent, selective and orally active.
- In BRCA2-deficient DLD-1 cells it was antiproliferative and boosted olaparib, with no effect in HR-proficient cells; chronic oral dosing with olaparib regressed xenografts.
A polymerase-domain inhibitor that is both oral and selective for the HR-deficient setting is what this target has been missing. The HR-proficient null result is the key control, so I'd now look at resistance and how it stacks against the helicase-domain approaches.
Sulfonium-modified pneumocandins overcome Cryptococcus' intrinsic echinocandin resistance
- Covalent sulfonium modification of the natural pneumocandin B0 scaffold gave derivatives active against Candida and able to reverse innate Cryptococcus neoformans resistance (MIC as low as 2 μg/mL).
- The modification raised fungal membrane permeability and caused depolarization while strengthening glucan synthase inhibition.
- Leads 3h and 5h showed low resistance potential, good safety and PK, and in vivo antifungal efficacy.
Echinocandins have never covered Cryptococcus, so adding a membrane-active cationic handle to restore activity is a smart reuse of a validated scaffold. The risk is that membrane disruption narrows the selectivity window, so host-cell toxicity data and the mechanism split deserve a close read.
Isoform-selective ULK1 PROTAC gives longer autophagy suppression than an inhibitor
- ATP-competitive inhibitors struggle to separate ULK1 from the near-identical ULK2, so the authors built cereblon-recruiting degraders instead.
- Structure-guided optimization gave MR-9036, which degrades ULK1 without touching ULK2 or IMiD neo-substrates, with ternary complex formation and proteasome dependence confirmed.
- After compound washout it kept autophagy suppressed longer than the clinical ULK1/2 inhibitor DCC-3116, with antitumor activity in KRAS G12C NSCLC models.
Selectivity between paralogs is where degraders can beat occupancy-driven drugs, and this is a clean example. What I'd check next is whether ULK2 compensation shows up in vivo, and whether washout durability holds in a model with realistic drug exposure rather than a pulse.
2026-10-08 3 articles
Tuned lanosterol derivative crosses the BBB and curbs Aβ burden in AD mice
- Lanosterol inhibits protein aggregation but has poor physicochemical and PK properties, so the authors tuned the hydrophilic–lipophilic balance around the 3-hydroxyl and the aliphatic side chain.
- Systematic screening gave compound 10, with markedly better metabolic stability and drug-like properties.
- Oral dosing of 10 rescued memory deficits and reduced Aβ burden in an Alzheimer's mouse model.
Natural-product sterols rarely survive their first PK table, so getting oral CNS exposure by tuning polarity around the 3-OH and side chain is the part I'd borrow. The open question is mechanism: efficacy in one mouse model is easy to over-read, and I'd want target engagement and sterol-pathway off-target data before getting excited.
Chiral imidazoquinolines show stereochemistry-dependent TLR7/8 agonism and antagonism
- A library of chiral imidazoquinolines was made and profiled in HEK-Blue hTLR7 and hTLR8 reporter assays.
- The SAR identified a potent dual TLR7/8 agonist and, from the same family, a dual antagonist.
- Activity depended on stereochemistry, likely because the two enantiomers interact differently in the TLR7/8 binding pocket.
Seeing both an agonist and an antagonist come out of one imidazoquinoline family, steered by stereochemistry, is a good argument for making both enantiomers early. For an adjuvant or autoimmune program, that switch is useful, but reporter-cell data alone only gets it to a hit; cytokine profiling in primary cells would tell me whether it holds up.
Patent highlight: carboxamide PKMYT1 inhibitors for replication-stress cancers
- PKMYT1 restrains CDK1 at the G2/M checkpoint, and blocking it forces premature mitotic entry, DNA damage accumulation and cancer cell death.
- The patent overview covers the design, synthesis and therapeutic potential of a new carboxamide-based inhibitor series.
- The authors note potential to enhance ATR inhibitors, PARP inhibitors, chemotherapy and radiotherapy.
This is patent-literature triage rather than data, so I read it as competitor intelligence: a carboxamide chemotype arriving in a PKMYT1 field already crowded with quinazolines says IP space is being carved up fast. I'd go straight to the examples to check the hinge binder and how hard the series leans on the PARP/ATR combination angle.
Novel Carboxamide-Based PKMYT1 Inhibitors for Replication Stress-Associated Cancers ↗
2026-10-07 5 articles
A macrocyclic BI-4020-based PROTAC degrades C797S-resistant EGFR
- HQY1480 is a PROTAC built on the macrocyclic fourth-generation EGFR inhibitor BI-4020, with the linker and E3 ligand optimized systematically.
- It degraded several clinically relevant EGFR mutants at low nanomolar concentrations, and proteomics showed no detectable off-target degradation.
- It outperformed BI-4020 in xenografts, including osimertinib-resistant models, and degraded EGFR in patient-derived xenografts.
Starting from a macrocycle rather than a classical TKI is the smart move: it sidesteps the poor PK and selectivity that EGFR PROTACs usually inherit from their warheads. I'd want to see how the degrader holds up against compound-specific resistance mutations, and whether the favorable PK survives scale-up beyond mouse.
Cyanoquinoline HIPK4 inhibitors open a route to non-hormonal male contraception
- HIPK4 is a spermatid-specific kinase needed for sperm head shaping, making it a candidate non-hormonal contraceptive target.
- A cyanoquinoline series gave potent, HIPK4-selective inhibitors, selective within the HIPK family and across the kinome.
- Some compounds also altered HIPK4 proteostasis in spermatids, causing insoluble aggregates and recruiting the autophagy receptor TAX1BP1.
A selective kinome-wide profile from a first series is what a probe needs, and the unexpected proteostasis effect is the intriguing bit: it hints at a degrader-like mode that could be tuned. For contraception the bar is brutal, though, with reversibility and long-term safety to prove.
Small-Molecule Modulators of HIPK4 Activity and Proteostasis ↗
OGG1 'organocatalytic switches' reprogram DNA repair to protect mitochondria
- Most OGG1 work has aimed at inhibitors; these mitochondria-enriched ORCAs instead reprogram the enzyme's catalysis.
- Biochemistry, mutagenesis and X-ray crystallography showed active-site binding that favors beta-elimination over glycosylase turnover.
- ORCAs protected mitochondrial function under oxidative stress, raised NAD levels in cortical neurons and were neuroprotective in a retina axotomy model.
Activating rather than inhibiting an enzyme is rare and hard to do, so a crystal structure showing the mechanism is what makes this credible. The open question is long-term safety: pushing a repair enzyme to a different catalytic outcome could create unusual DNA lesions, and the neuroprotection data are still early.
Development of Organocatalytic Switches of OGG1 that Protect Mitochondria under Oxidative Stress ↗
4-Aminoquinazoline PKMYT1 inhibitors cut H-bond donors for CCNE1-amplified tumors
- A hydrogen-bond donor-to-acceptor conversion was used to lower the donor count of a 4-aminoquinazoline PKMYT1 series and improve drug-likeness.
- Lead 12f was a nanomolar enzyme inhibitor, potent in OVCAR-3 ovarian cells and synergistic with PARP inhibitors.
- With acceptable oral PK, it showed efficacy in an OVCAR-3 xenograft and was well tolerated.
Trimming HBDs is a clean, transferable tactic for improving permeability and oral exposure in a kinase series. The PARP-inhibitor synergy is the commercially interesting part, but PKMYT1 is crowded, so I'd check selectivity against other kinases and how 12f compares with the clinical frontrunners.
Istradefylline-derived thienopyrimidinones give an oral NLRP3 inhibitor for colitis
- The anti-Parkinsonian drug istradefylline showed modest NLRP3 inhibition, and optimizing it gave a thienopyrimidinone series.
- Lead L22 was roughly tenfold more potent than istradefylline, bound the NLRP3 NACHT domain directly and blocked inflammasome assembly.
- It was orally bioavailable, eased symptoms in a DSS colitis model and looked safe in acute and subacute toxicity studies.
Starting from a marketed drug's off-target activity gives a head start on drug-likeness, and direct NACHT-domain binding is what you want to see. NLRP3 is a busy field, so the real test is how L22 compares with clinical-stage inhibitors on potency and brain or gut exposure.
2026-10-06 4 articles
Structure-based medicinal chemistry yields potent pan-YTHDF m6A reader ligands
- YTHDF1, YTHDF2 and YTHDF3 read m6A-modified mRNA in the cytosol, and this preprint reports a protein structure-based medicinal chemistry campaign against them.
- The aim is ligands that bind all three paralogs, rather than one reader at a time.
- Only the abstract opening was accessible, so potency and cellular data are not covered here.
The YTH domains' aromatic cage is a tough, charged pocket, so any structure-guided progress on it is worth tracking. A pan-paralog ligand is a sensible choice, given the redundancy among the three readers. I'd want selectivity over YTHDC1/2 and evidence of cellular target engagement before calling this a probe.
Pyridazine nicotinamides as a new FTO inhibitor chemotype for AML
- A 67-compound SAR campaign on pyridazine-containing nicotinamides gave E6 as the most active FTO inhibitor, with binding confirmed by MST, CETSA and DARTS.
- E6 was active against MOLM-13 cells, raised global m6A, upregulated ASB2 and RARA and lowered c-Myc.
- It showed acceptable CYP safety and PK and inhibited MOLM-13 xenograft growth.
Another FTO series, but the useful part is the new scaffold: FTO chemotypes are still thin, and most earlier ones lean on the same few motifs. Potency is modest, so I'd treat E6 as a starting point and look for selectivity over ALKBH5 and other AlkB family members before reading too much into the cell phenotype.
One atom flips a CRBN degrader from NSD2-selective to GSPT1-selective
- Starting from LLC0424, an NSD2 degrader that also engages GSPT1, a single-atom change gave two close analogues: 424-ND (NSD2-selective) and 424-GD (GSPT1-selective).
- 424-ND suppressed androgen receptor signaling in prostate cancer cells, while 424-GD triggered the integrated stress response.
- Biolayer interferometry showed distinct ternary-complex cooperativity for each target, and simulations suggested different low-energy conformations explain the bias.
Degrader selectivity here tracks ternary-complex cooperativity, not binary affinity, which is exactly what I'd want to see in an SAR table. A matched pair this tight is a ready-made probe set for NSD2 and GSPT1. I'd check proteome-wide selectivity and whether the cooperativity trend holds in cells.
Single-Atom Modification Enables Reversal of Degradation Selectivity between NSD2 and GSPT1 ↗
Azide-bearing VEGFR2 inhibitors switch on under green light in the retina
- Azido-functionalized VEGFR2 inhibitors EYE1090 and EYE1118 bind the receptor in a light-triggered way while staying potent in the dark.
- Green light that reaches the human retina, including in older eyes, boosted their anti-angiogenic activity in vitro.
- Given orally, both suppressed VEGF-induced retinal leakage in rats and shrank lesions in a mouse choroidal neovascularization model without acute liver toxicity.
An azide as the photo-switch is a neat, small-footprint handle on a classic kinase scaffold. The appeal is spatial selectivity: systemic exposure with activity concentrated where light focuses. I'd probe how much dark activity remains, which matters for off-target VEGFR2 effects elsewhere, and the photoproduct's fate.
Three Nitrogen Atoms Turn Old Kinase Inhibitors Into New Targetable Remedy ↗
2026-10-05 4 articles
Oral isoindolinone GSPT1 glue degrader LG-NE-29 targets glioblastoma models
- A viability-based phenotypic screen flagged GSPT1 as a vulnerability in glioblastoma cells, where resistance to temozolomide arises quickly.
- Optimizing an isoindolinone series for metabolic stability gave LG-NE-29, a molecular glue that drives CRBN-dependent ubiquitination and proteasomal degradation of GSPT1.
- It is reported to avoid the metabolic weaknesses of earlier scaffolds, and to be orally bioavailable with activity in glioblastoma xenograft models.
Isoindolinone CRBN glues usually die on metabolism, so fixing that liability is the real story here. Before I believe it, I'd want the GSPT1 DC50/Dmax, proteome-wide selectivity (IKZF1/3, other neosubstrates), and oral PK with brain exposure. GSPT1 degradation is also broadly cytotoxic, so the therapeutic window in normal cells matters.
First synthetic PAPP-A inhibitors dampen IGF-1 signaling in cells and in vivo
- PAPP-A is a secreted metalloproteinase that cleaves IGF-binding proteins to control local IGF signaling, offering an alternative to IGF-1R targeting.
- Inhibitors were built on an IGFBP-5-derived anchor sequence, with the scissile bond replaced by phosphinate or phosphonate groups, giving potent and selective compounds.
- Cryo-EM showed how they bind the active site, and they blocked IGFBP-4 and IGFBP-5 cleavage.
- They suppressed IGF-1 signaling in A549 cells, comparably to stanniocalcin-1, and inhibited Papp-aa-dependent signaling in vivo.
Swapping the scissile bond of an IGFBP-5 anchor sequence for a phosphinate or phosphonate is classic transition-state mimicry, and a cryo-EM pose would validate the zinc-binding hypothesis. Going after the protease rather than IGF-1R is smart for selectivity. I'd want Ki values against related metalloproteinases, and cell permeability and stability of these peptidic leads, before trusting the in vivo claim.
KPB82, a ceramide-mimetic sulfonamide, is a selective ACER2 inhibitor in a bioRxiv preprint
- ACER2 hydrolyses ceramides to sphingosine and fatty acids, and no pharmacological tool for it existed.
- KPB82, a dodecane sulfonamide carrying a ceramide-like hydroxyphenylpropyl group, inhibited ACER2 potently, with minimal activity on acid and neutral ceramidases and none on ACER1 or ACER3.
- Kinetics were competitive, and docking into an AlphaFold3 model placed it in the substrate pocket near the Zn2+-binding histidines.
- The title reports protection of tumor and primary cells from doxorubicin cytotoxicity.
No ACER2 tool compound until now, so a competitive, ACER1/ACER3-sparing hit matters. A dodecane sulfonamide with a hydroxyphenylpropyl headgroup reads like a ceramide mimic, and the docked pose near the Zn2+ histidines is only an AlphaFold3 hypothesis. I'd want IC50s, an SAR series, and cellular target engagement before trusting the doxorubicin rescue.
Cyclooctyne click triggers Cope elimination to unmask Michael acceptor warheads and release payloads
- Michael acceptors are masked with a hydroxylamine; a bioorthogonal reaction with a cyclooctyne triggers Cope elimination, regenerating the electrophile under mild conditions.
- The approach covers several warhead types, including unsaturated carbonyl, cyano, sulfonyl, phosphonate and maleimide, with tunable activation rates.
- Functionalized cyclooctynes can release an imaging or functional payload at the same time, giving a signal that reports activation.
- Applied to covalent inhibitors, it gave controlled activation in cells.
Could a masked warhead finally fix the off-target reactivity of acrylamide-class leads? Caging the Michael acceptor as a hydroxylamine and uncaging it by cyclooctyne click is a neat way to turn on covalency only where you dose the trigger. From the abstract alone I would want the rate constants, whether the hydroxylamine-bearing prodrug keeps target affinity, and how the cyclooctyne's size and lipophilicity compare with a conventional warhead.
2026-10-04 4 articles
Aryl alkyl ether CD73 inhibitor LB10 is orally active in a lung cancer model
- CD73 is the rate-limiting enzyme of the adenosine pathway and a tumor-immunosuppression target.
- An aryl alkyl ether series was designed; LB10 emerged as the most promising, potent in both biochemical and cell assays.
- Enzyme kinetics and co-crystallography confirmed competitive inhibition.
- LB10 had low cytotoxicity and good pharmacokinetics, and oral dosing curbed tumor growth in a syngeneic Lewis lung carcinoma model, alone or in combination.
Non-nucleotide CD73 inhibitors that stay orally bioavailable are the part I care about: most potent early chemotypes were AMP-like and carried the usual permeability and clearance baggage. A co-crystal confirming a competitive mode gives a clean starting point for SAR around the ether linker. I would want to see how it behaves against the soluble versus membrane-bound enzyme and in human-relevant adenosine readouts before getting excited.
Can ternary-complex scoring rank close PROTAC linker analogues? A matched-pose test
- Linker optimization in targeted protein degradation is still largely empirical.
- The preprint asks whether current computational methods can rank close linker analogues before synthesis, the finest chemical differences yet tested.
- It uses a matched-pose design on VHL-recruiting SHP2 degraders to isolate the effect of the linker.
- This is a preprint, not yet peer reviewed; the snippet-level abstract available limits detail on the outcome.
Linker tweaks are where PROTAC campaigns burn months of synthesis, so an honest test of whether scoring can separate near-identical analogues is more useful than another headline-grabbing benchmark. Matched poses remove the usual excuse that the method just got the geometry wrong. Even a negative answer helps: it tells us to keep building degradation and cooperativity assays rather than trusting a docked score.
Bispecific GTACs antagonize GPCRs by sending them to the lysosome
- GPCR–TfR1 targeting chimeras (GTACs) are bispecific antibodies that pair a receptor binder with a transferrin-receptor binder.
- They drive endocytosis and lysosomal degradation of the GPCR, rather than blocking the orthosteric site.
- Reported for BILF1, RXFP1 and CCR6, covering viral, cancer and immune targets that are hard to drug.
- Signalling, including constitutive activity, was fully shut down, with markedly greater potency than conventional antibody antagonists.
Degrading the receptor sidesteps the usual GPCR headache of finding a clean orthosteric or allosteric small molecule, and it kills constitutive signalling that inverse agonists only partly touch. The catch for my own work: it is an antibody format, so oral exposure and tissue reach are off the table, and TfR1 recruitment brings its own distribution and safety questions. Still, it hands us a genuine alternative mechanism for orphan-like GPCRs where chemistry has stalled.
GPCR antagonism via rewiring of receptor trafficking and degradation ↗
Soft drugs: building rapid, predictable inactivation into topical therapies
- Review of soft drug design: molecules built to be rapidly and predictably inactivated by metabolism after acting.
- Typically close analogues of a validated lead, with a hydrolytically labile group (often an ester) as the deliberate soft spot.
- Highlights topical soft drugs in development, where local skin activity and low systemic exposure are the goal.
- Also covers practical considerations, open challenges and future directions.
For anyone optimizing a topical lead, the useful message is that the metabolic soft spot is a design input, not a liability to be hunted down late. Tuning ester lability so the compound survives in skin but clears quickly in plasma is a tractable, SAR-friendly problem, and it sidesteps a lot of systemic safety work. The risk is the usual one: inter-species and skin-versus-blood esterase differences can make preclinical clearance misleading.
2026-10-03 6 articles
Bifunctional OGTACs steer OGT to install O-GlcNAc on chosen proteins
- OGT/OGA inhibition affects thousands of substrates, so protein-specific O-GlcNAc functions are hard to assign; OGTACs address this by recruiting OGT to a chosen protein.
- Each OGTAC joins an OGT-engaging element, a linker and a target-recognition motif, and can partly bypass TPR-domain substrate recognition.
- Productive O-GlcNAc writing needs proper ternary-complex formation and noninhibitory OGT binding, while the target-recognition motif sets targetable scope and selectivity.
- Local installation is linked to changes in protein turnover, signaling and transcription.
The OGT-binding warhead is the make-or-break piece here: if it inhibits OGT, you lose the very activity you're trying to redirect, so noninhibitory binders are the real SAR hurdle, much as with E3 ligands in degraders. I also like that the target-recognition motif, not OGT's TPR domain, sets selectivity, which makes this modular. It's an Accounts-level overview, so I'd want to see how well the chimeras hold up across targets before getting excited.
Chemically Induced Proximity for Targeted Protein O-GlcNAcylation ↗
Coiled-coil masks keep T cell engagers silent until tumor proteases cut them loose
- Anti-CD3 Fabs (OKT3, UCHT1) are sterically masked by leucine-zipper coiled-coil domains fused through protease-cleavable linkers, and paired with PSMA- or HER2-targeting nanobodies.
- Masking strongly lowered CD3 binding, and protease cleavage restored most of it, both on recombinant CD3 and on T cell-displayed CD3.
- Masked constructs did not activate Jurkat cells, whereas unmasked ones did.
- MMP2-cleavable versions drove MMP2-dependent killing of PSMA+ and HER2+ cancer cells in PBMC co-cultures, aiming to limit on-target off-tumor toxicity.
The appeal is that the mask is modular: swap the cleavable linker and the same leucine-zipper scaffold could, in principle, be retuned to a different protease, which is more flexible than hard-wiring one design. What I would press on is the gap between cleaved and unmasked binding, since 'most' restored is not full, and MMP2 is not strictly tumor-restricted. Only Jurkat and PBMC co-cultures here, so the off-tumor safety claim is still an aim, not data.
Entrance-channel design tames cytotoxicity of the JK-4b NNRTI lead
- JK-4b, a potent NNRTI active against wild-type and clinical HIV-1 variants, was shelved because of high cytotoxicity; the authors used it as a lead for new analogues.
- Structure-guided designs addressing the NNRTI entrance channel gave a series with lower cytotoxicity and improved selectivity.
- Lead compound 9n retained strong potency against common resistance mutants, including double mutants, at levels comparable to etravirine.
- 9n also showed minimal cytochrome P450 inhibition and good human liver microsome stability, supporting further development.
Rescuing a shelved lead is always more interesting than starting cold: JK-4b already had the potency and resistance coverage, so the real question was whether entrance-channel contacts could decouple that from its cytotoxicity. If 9n's profile holds up, that suggests the toxicity was scaffold-tunable, not baked into the pharmacophore. Matching etravirine on double mutants while staying clean on P450 and microsome stability is what I'd want to see before making more.
What first-generation oral GLP-1 drugs teach about designing the next ones
- Reviews nonpeptidic GLP-1 receptor agonists that reached the clinic, including danuglipron, lotiglipron, DA-302168S and orforglipron, as case studies of how each solved the oral-delivery problem.
- Notes the design challenges these first-generation molecules still leave open.
- Proposes next-generation approaches: peptidomimetic design, multi-target agonists, and exploiting orthosteric-allosteric cooperativity.
- Covers practical aspects such as screening cascades, preclinical species choice, formulation and early safety assessment, with relevance to other difficult GPCRs.
Four clinical chemotypes, four different answers to the same problem: a class B GPCR built to bind a large peptide. What I want from a review like this is the SAR logic behind each survivor. Orthosteric-allosteric cooperativity is the idea I'd chase, since it could loosen the potency-versus-permeability tradeoff. Whether it holds up depends on the screening cascade and species choice, which is where programs usually stumble.
Shutting down JNK signaling resensitizes KRAS G12D-resistant pancreatic cancer cells
- Pancreatic cancer cells that adapt to KRAS G12D inhibition can be pushed back toward sensitivity by suppressing the JNK pathway more completely.
- Selective covalent inhibitors of MAP2K4, MAP2K7, or both were used to probe how much JNK suppression is needed.
- Stronger JNK blockade disables the feedback loop that reactivates KRAS signaling in resistant cells.
- Inhibitor-sensitive cells gain no benefit, so the vulnerability is specific to the resistant state.
If this holds up, the interesting part is the logic: resistance to a KRAS G12D inhibitor runs through JNK feedback, so you hit the node that rewires the pathway, not KRAS again. Covalent engagement of MAP2K4 and MAP2K7 is a neat way to ask how deep the suppression must be, though kinase selectivity between the two will be the real SAR headache. Sparing sensitive cells is the encouraging bit; it's abstract-level so far.
Structure-guided design yields selective wild-type KIT inhibitors that avoid class III RTK off-targets
- Close ATP-site similarity across class III receptor tyrosine kinases makes selective KIT inhibition hard; this work tackles it with structure-guided optimization.
- A triazolopyridine hinge binder gave a selective start, and a central linker change led to a reverse arylacetamide series with better potency and pharmacokinetics.
- A pyrazole linker and hinge-motif edits kept potency in human serum, while terminal aryl tuning reduced CYP time-dependent inhibition and sharpened kinome selectivity.
- Crystal structures showed that linker stereoelectronics near the gatekeeper can drive selectivity, yielding a lead suited to chronic therapy.
The linker, not the hinge binder, is what caught my eye: stereoelectronics near the gatekeeper apparently buy selectivity that ATP-site similarity across class III RTKs would otherwise deny. That is a handle worth stealing for other crowded kinase families. I also like that CYP time-dependent inhibition and human-serum potency were fixed in the same campaign, which reads like a lead meant for chronic dosing.
2026-10-02 7 articles
Native MS Shows PROTAC Linker Length and Warhead Identity Shape Ternary Complexes Differently
- Ion mobility, surface-induced dissociation and variable-temperature ESI were combined to probe BRD4–PROTAC–VCB complexes built with two BET ligands (JQ1 and I-BET726) and PEG linkers of different lengths.
- Shorter linkers held complexes in more extended shapes; longer, flexible linkers allowed relaxed, native-like conformations.
- JQ1 complexes tended to eject the PROTAC under collision, while tighter-binding I-BET726 complexes retained it; the two also melted differently.
Linker optimization is still mostly empirical, so orthogonal readouts of how architecture shapes the complex interface are welcome. Gas-phase data are not solution cooperativity, and I'd not rank degraders by them alone, but pairing them with cellular degradation could help rationalize why two warheads behave so differently. A preprint, so treat the conclusions as provisional until peer review.
A Quinazoline Nav1.7 Lead, Absolute Configuration Fixed by MicroED, Shows Oral Analgesia in Rodents
- Starting from a modest focused-library quinazoline hit, SAR across about twenty analogs gave a chiral lead with sub-micromolar potency and clear selectivity over Nav1.5.
- The absolute configuration was assigned by MicroED, so the active enantiomer is unambiguous without large crystals.
- The lead had acceptable oral exposure, reduced pain behavior in two rodent models, and was clean in a 44-target off-panel; Nav1.7-knockout neuron controls support on-target action.
Nav1.7 has burned a lot of programs on selectivity and translation, so a clean off-target panel plus knockout-neuron controls is what I'd look at first. Potency is still modest and the dose needed is high, so this is a starting scaffold rather than a candidate. The practical takeaway is MicroED: assigning chirality from nanocrystals of an early lead saves weeks of enantiomer chasing.
p300/CBP Drug Discovery: Do Bifunctional Degraders Now Beat Classical Inhibitors?
- A perspective reviewing small-molecule inhibitors of the p300/CBP bromodomain and catalytic (HAT) domain, with emphasis on how the leading clinical compounds were optimized.
- It then follows the field's shift toward bifunctional proximity-inducing molecules, including PROTAC degraders.
- The article compares what each modality offers for these large, multidomain coactivators.
p300/CBP is a good test of when degradation earns its molecular weight: scaffolding functions that inhibitors leave intact are exactly what a degrader removes. The HAT-domain and bromodomain optimization stories are useful reading for anyone with a stubborn chromatin target. I'd read the degrader sections skeptically on paralog selectivity, since p300 and CBP are nearly identical.
Direct-to-Biology Screening Yields a GRP78 Inhibitor That Spares Other HSP70 Isoforms
- Isoform selectivity within the highly conserved HSP70 family is notoriously hard; the team targeted the peptide-binding pocket of GRP78's substrate-binding domain.
- A direct-to-biology workflow, testing crude library reactions without purification, pointed to compound 12.
- It engages GRP78 in biochemical, biophysical and cellular thermal shift assays, is selective over other tested HSP70s, and perturbs unfolded protein response signaling with selective killing of A549 cells.
Going after the substrate pocket rather than the ATP site is the sensible way to buy HSP70 selectivity, and D2B makes iterating on it cheap. The cell-line-selective killing is the part I'd treat cautiously: it could reflect UPR dependence or something off-target. Orthogonal engagement data like CETSA are encouraging; I'd want a close inactive analog next.
Development of Isoform-Selective GRP78 Inhibitors from a Direct-to-Biology Strategy ↗
A '2-in-1' PROTAC Folds the Cereblon Ligand into the HDAC8 Cap to Shrink the Degrader
- Instead of tethering two ligands, the cereblon-binding motif is built into the capping group of an HDAC8 inhibitor, so one structural element engages both proteins.
- Versus the group's first-generation degrader, the compact analogs are smaller, more selective and more drug-like.
- They degrade HDAC8 potently in vivo.
Most of us accept PROTAC bulk as a tax; fusing the E3 ligand into the warhead's cap group attacks that directly and is a transferable idea for other zinc-enzyme targets. The question I'd press is whether the shared motif compromises either binding event or cereblon neosubstrate selectivity. If in vivo degradation holds with better properties, the 'linkerless' direction deserves more attention.
A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗
BmTACs Ride Age-Upregulated Transcytosis to Deliver a ROS-Activated DAPK1 Degrader into the Brain
- Brain delivery is the main barrier for degraders in neurodegeneration; BmTACs attach a macrocyclic peptide shuttle that exploits caveolae-mediated transcytosis, which rises with age in brain endothelium.
- A reactive-oxygen-species-responsive cage on the VHL ligand keeps the PROTAC inactive until it reaches high-ROS tissue.
- The platform is designed to remove activated DAPK1 selectively in the aging brain.
Two gating layers, shuttle for entry and ROS cage for activation, is clever systems design, but it moves the problem from medicinal chemistry to conjugate CMC and PK. I'd look hard at the unmasked-PROTAC fraction in periphery and at the shuttle's dependence on aged-endothelium biology, which could narrow the patient window. A real step for CNS degraders if the in vivo data hold up.
DT-9081: Scaffold Hopping Delivers an Oral EP4 Antagonist That Has Cleared Phase I
- EP4 blockade is an immuno-oncology idea built on PGE2-driven immune suppression in tumors.
- Scaffold hopping gave a new chemical series with better activity and pharmacokinetics, and SAR work led to DT-9081.
- It combines potent antagonism, favorable ADME and a clean preclinical safety profile, and has completed a phase I monotherapy trial in solid cancers.
This paper is the full med-chem story behind a compound that already has human data, which is rarer and more useful than most 'discovery of' papers. EP4 is crowded, so the interesting part is how the new series differentiates on PK and safety against earlier antagonists. I'd read it for the scaffold-hop logic and watch whether phase I translates into combination activity with checkpoint blockade.
2026-10-01 6 articles
Aryl Sulfamates Get a Systematic SAR Look as Carbonic Anhydrase IX Binders
- Ortho- and meta-substituted aryl sulfamates were synthesized and profiled by thermal shift, enzyme inhibition and a live-cell competition assay against CA IX, the isozyme overexpressed in hypoxic solid tumors.
- The best compounds bound CA IX with very high affinity, and X-ray structures with several isozymes identified the groups driving affinity and selectivity.
- pH-dependent binding data indicate the deprotonated, negatively charged sulfamate nitrogen coordinates the active-site zinc.
CA inhibitors are dominated by sulfonamides, so a clean sulfamate SAR backed by crystal structures is useful chemotype diversification. Selectivity over the ubiquitous CA I and II is what sinks tumor-CA programs, and the co-crystals give a concrete handle on it. Live-cell competition data beat purely recombinant assays, but I'd want hypoxic-cell potency and physicochemical properties before calling these lead-like.
Structure-Affinity and Selectivity of Aryl-Sulfamates as Inhibitors of Carbonic Anhydrase IX ↗
Covalent Cyclitol Aziridines Deliver a Brain-Penetrant, Selective GBA2 Inhibitor
- GBA2 has lacked inhibitors that separate it from GBA1 and glucosylceramide synthase; the team built a focused library of electrophilic cyclitols (epoxides, cyclic sulfates, N-alkyl aziridines) from earlier β-D-arabinofuranose activity-based probes.
- Profiling against GBA1, GBA2, GBA3 and glucosylceramide synthase identified covalent inhibitors selective for GBA2.
- The lead is reported as the first brain-penetrant covalent inhibitor to selectively inactivate GBA2 in vivo.
Turning an activity-based-probe scaffold into an in vivo tool compound is a neat path, and selectivity over GBA1 and GCS is precisely what GBA2 biology has been missing. For anyone working on sphingolipid or lysosomal storage disorders this is a usable tool. My open question is the covalent off-target profile at in vivo exposure, since aziridines are not quiet electrophiles.
Structure-Guided RXFP4 Agonists Stay in the Gut and Ease Constipation in Mice
- Guided by the cryo-EM structure of RXFP4, the authors built a tetrahydroisoquinoline agonist series aimed at two hurdles: close homology to RXFP3 and the need for gut-restricted exposure.
- Lead compound 44 was a potent agonist with strong selectivity over RXFP3 and a pharmacokinetic profile heavily skewed toward ileum over plasma.
- Oral dosing was effective in a loperamide-induced constipation mouse model.
Getting a small molecule onto a peptide-GPCR whose paralog looks nearly identical is the hard part, and using the cryo-EM structure to buy RXFP3 selectivity is the right play. The gut-over-plasma skew is what I'd look at first, since a locally acting agonist sidesteps systemic liabilities. I'd still want permeability, efflux and metabolic stability data behind that ileum exposure.
Azaphilone Probe Maps Reactive Lysines Across Live Bacterial Proteomes
- SCL-alkyne, a simplified azaphilone derived from the natural product sclerotiorin, was designed to profile lysine reactivity proteome-wide in bacteria.
- It was highly lysine-selective in vitro and in live E. coli; most engaged sites were lysines or protein N-termini, and only a small subset of reactive lysines sat in functional regions.
- Enrichment analysis pointed to bacterial chemotaxis as a major target pathway, which was then confirmed.
Covalent ligand discovery has been cysteine-centric, and lysine-directed scaffolds beyond sulfonyl fluorides and activated esters are scarce, so a natural-product-derived option is appealing. The observation that few reactive lysines are functional is a sober reminder that reactivity is cheap and function is not. As an E. coli preprint it is a starting point for covalent fragments, not a lead.
Three Chemoselective Routes Turn Cereblon PROTACs into Cleavable Prodrugs
- Cereblon-recruiting PROTACs are hard to derivatize for prodrug delivery; the paper offers three orthogonal handles: triazole quaternization, tertiary-amine alkylation and a hydroxyl linker.
- The approaches give cleavable prodrugs with tunable release kinetics, compatible with PEGylated constructs and bottlebrush prodrugs.
- Representative examples showed controlled degrader release, in vitro anticancer activity, tumor accumulation and preliminary in vivo efficacy.
The real PROTAC problem is exposure rather than ternary-complex cooperativity, so a modular way to mask and release them is overdue. Chemoselectivity on a glutarimide-bearing molecule is the practical point: if it works on existing degraders without re-optimization, it is genuinely reusable. I'd check release in plasma versus tumor, and whether the masked forms avoid premature cereblon engagement.
Generalizable Strategies for the Synthesis of Cereblon-Recruiting PROTAC Prodrugs ↗
Open Screening Dataset Maps Small-Molecule Inhibitors Across Nine Human DNA Glycosylases
- A Scandinavian consortium built a high-throughput biochemical assay platform for human DNA glycosylases, the eleven enzymes that initiate base excision repair.
- A chemogenomic library was screened against nine glycosylases with assays good enough for hit calling, yielding primary and concentration-response data and several previously unreported inhibitors.
- All data, protocols and metadata are publicly available.
Glycosylases have been chemically neglected, so an open, annotated screen across nine of them is starting material a hit-finding team can mine directly. Chemogenomic libraries carry target annotations, which helps with mechanism and selectivity reads. I'd immediately cross-check the hits for assay interference and DNA-binder artifacts, since nucleic-acid enzyme screens are notorious for them.
A high-throughput screening dataset of small-molecule inhibitors across human DNA glycosylases ↗