SAR & lead optimization
70 articles
Kinase Inhibitor Reshapes Its Own Binding Pocket to Gain Selectivity
- Researchers led by Seidler and colleagues designed a small-molecule inhibitor of p38δ (p38 delta), a MAP kinase linked to cancer, and reported its binding mechanism in Angewandte Chemie International Edition.
- Structural analysis showed the inhibitor initially collided with a flexible loop lining the kinase's ATP-binding pocket, a clash that would normally be expected to weaken or block binding.
- Instead of being excluded, the inhibitor caused that loop to change conformation and fold around the molecule, producing an unusually tight, self-encapsulating fit within the remodeled pocket.
- The authors present this induced-fit, pocket-remodeling behavior as a previously undescribed route to kinase selectivity, distinct from conventional structure-based design, which treats the binding pocket as a fixed template the inhibitor must be shaped to match.
- The finding suggests that deliberately exploiting pocket flexibility, rather than avoiding steric clashes, could become a strategy for engineering selectivity in future kinase-targeted drug design.
The steric clash was the feature, not the bug — that's the part that makes me sit up. We're trained to treat the ATP pocket as a fixed template and design ligands to fit it; here the loop folded around the inhibitor and the "bad" collision became the selectivity handle. That inverts the whole lock-and-key mental model. Selectivity-wise, this is a genuinely new lever. Everyone's chasing hinge tweaks, DFG-out, or allosteric pockets — induced self-encapsulation is a different axis entirely, and worth stealing for other kinase programs. My skepticism: is this designable, or did they get lucky in one series and rationalize it after the crystal structure came back? Rational pocket-remodeling on demand would be huge; a one-off induced-fit anecdote is just a nice paper. Also worth noting: p38δ is far less drugged than p38α, so any new selectivity trick here has real headroom.
Modular H-Phosphonate Platform Opens New Route to Backbone-Modified Oligonucleotides
- Oligonucleotide backbone chemistry gets a new modular entry point: an H-phosphonate diester dinucleotide 'blockmer' platform that builds backbone-modified oligonucleotides through standard solid-phase synthesis.
- The method exploits the ambiphilic reactivity of H-phosphonate diesters, allowing diverse phosphate backbone modifications to be installed without air- or moisture-sensitive P(III) reagents or hazardous chemicals.
- Accessible backbone modifications span a wide range, from simple alkyl substitutions to sulfonamide-linked phosphate analogs, well beyond conventional phosphorothioate-type chemistries.
- Because the dinucleotide blockmers are compatible with existing solid-phase assembly workflows, they can be combined and positioned flexibly within a single oligonucleotide sequence.
- The platform is designed to enable systematic backbone structure-activity relationship studies in oligonucleotide drug discovery, providing a scalable and robust route for rapid analog generation.
H-phosphonate diesters as bench-stable P(III) surrogates is the headline: no more babysitting moisture-sensitive phosphitylating reagents under inert atmosphere just to install a novel backbone linkage. Backbone modification has been the stubborn bottleneck in oligo SAR — everyone can vary the sugar or the base, but stepping outside phosphorothioate/phosphorodiester space usually means bespoke phosphoramidite synthesis for every single analog. Pre-made dinucleotide blockmers flip that: build a small library of linkage types once, then mix-and-match them like ordinary phosphoramidites on standard solid-phase cycles, placing modifications at any position in the sequence. For a team running iterative backbone SAR, that's the difference between a multi-week custom-monomer detour and a same-week analog set. Real question is whether coupling efficiencies and diastereomer control hold up across the full modification set, not just the showcase examples.
Dynamic Combinatorial Chemistry Delivers a Reversible, Sub-Picomolar Trivalent Thrombin Inhibitor
- A PNA-templated dynamic combinatorial chemistry (DCC) platform assembles a three-fragment library (~125,000 possible combinations) using DNA/PNA hybridization handles for unbiased equilibration.
- Thrombin itself templates the library, selecting and amplifying the best-binding fragment combination; size-exclusion filtration coupled with MALDI mass spectrometry gives a full selection-to-readout cycle in under an hour.
- The selected trivalent assembly engages thrombin's active site plus both exosites simultaneously, driving exceptionally high (sub-picomolar-range) binding affinity and near-stoichiometric inhibition.
- Unlike covalent thrombin inhibitors, binding is fully reversible — pharmacologically relevant for an anticoagulant, where reversibility matters for managing bleeding risk.
- Demonstrates target-templated DCC as a rapid route to multivalent, exosite-spanning inhibitors, even against a well-studied target.
Sub-picomolar affinity out of a 125,000-member DCC library gets my attention immediately — that's an avidity effect, not a single tight pocket, and it's essentially bivalirudin's active-site/exosite-1 logic pushed one contact further to include exosite II as well. Exosite engagement should also buy real selectivity over trypsin-like serine proteases that don't share thrombin's exosite topology, though I'd want that confirmed head-to-head against fXa and trypsin. My hesitation is tractability: a DNA/PNA-templated trivalent assembly is a fantastic proof-of-concept and chemical tool, not yet a lead — that's a long way from oral. Against DOACs' one-pocket, small-molecule simplicity, this wins on affinity and reversibility but loses badly on drug-likeness; the real test is whether target-templated DCC can be steered toward a druggable combination, not just the tightest binder.
Discovery of a Reversible Sub-Picomolar Thrombin Inhibitor Using DCC ↗
From Micromolar to Nanomolar: A First-in-Class B3GAT3 Inhibitor Emerges for Liver Cancer
- B3GAT3 (beta-1,3-glucuronosyltransferase) is overexpressed in hepatocellular carcinoma (HCC) and correlates with poor patient prognosis, marking it as a promising but previously untargeted anti-cancer target.
- The research team started from TMLB-C16, an in-house lead compound with micromolar-range inhibitory potency against B3GAT3.
- Using structure-guided design, they synthesized 60 novel derivatives built on a 6-methoxyquinoline-4-carboxamide scaffold, systematically probing structure-activity relationships (SAR).
- This optimization campaign identified TMLB-G9, a candidate whose potency improved dramatically, moving from the micromolar starting point to nanomolar activity.
- TMLB-G9 is reported as a first-in-class B3GAT3 inhibitor, offering a new chemical starting point for potential HCC drug development.
Glycosyltransferases have a reputation for being nearly undruggable — shallow, solvent-exposed active sites built to grip a UDP-sugar donor and a growing acceptor chain, not a cozy pocket for a small molecule. So any inhibitor reaching nanomolar here deserves a second look. 60 analogs to go from micromolar to nanomolar on one scaffold is a lean, efficient campaign — a couple of hot spots optimized, not a fishing expedition. The 6-methoxyquinoline-4-carboxamide is flat and stackable, which reads like it's wedging into a groove near the sugar-binding cleft rather than mimicking the full UDP-GlcA donor. My real worry is the B3GAT family — B3GAT1/2/3 share a fold, and no selectivity data has been shown yet. First-in-class glycosyltransferase inhibitors are still rare in oncology, so this is a genuine new tool, but 'first-in-class' this early just means untested against the paralogs that matter.
Re-Engineering a Toxic HIV Inhibitor into a Safer Lead
- Starting from JK-4b, a potent but overly cytotoxic non-nucleoside reverse transcriptase inhibitor (NNRTI), researchers pursued structure-guided optimization to fix its safety liability.
- Design efforts targeted the NNRTI entrance channel, a sub-pocket near the classical allosteric site, to reshape how analogs bind reverse transcriptase and reduce off-target toxicity.
- Structure-activity relationship (SAR) studies across this new series pointed to compound 9n as the standout, with markedly improved selectivity and much lower cytotoxicity than JK-4b.
- Despite the safety redesign, 9n kept potent antiviral activity against both wild-type HIV-1 and clinically relevant drug-resistant variants, preserving the lead's core strength.
- The work illustrates entrance-channel-focused chemistry as a practical strategy for detoxifying promising but toxicity-limited NNRTI candidates.
This mechanism is what caught my eye: if cytotoxicity in JK-4b traced to deep induced-fit distortion in the classical pocket, moving the pharmacophore to a shallower, more solvent-exposed sub-pocket is a clean way to keep the RT H-bond network while shedding the strain that drives off-target hits. Retained potency against resistant variants is the real tell — K103N/Y181C-type mutations cluster in the classical pocket, so if 9n still works, its binding mode isn't leaning on that contact set, which also argues the toxicity really was off-target, not a right-target dose-limiting problem. Practically, a solvent-facing channel is easier SAR real estate — more room to tune logP/solubility without wrecking the core pharmacophore, so this reads generalizable, not a one-off rescue. Prefer this over the usual toxicity fixes (metabolite masking, prodrugging) — it's addressing binding geometry, not just downstream liability.
Brain-Penetrant CD38 Inhibitors Show Dose-Dependent NAD+ Increase in Mice
- CD38 is an enzyme central to NAD+ metabolism and calcium signaling in cells, and interest has grown in targeting it for neurological and psychiatric conditions.
- The authors designed a new tricyclic chemical series that binds CD38 by forming an adduct with the ADPR co-substrate, inhibiting the enzyme through an uncompetitive mechanism.
- Locking the molecules into their active shape — achieved by covalently linking a six-membered heteroaromatic core to an imidazole warhead — boosted biochemical activity against both mouse and human CD38.
- Iterative tuning of the core and linker chemistry, guided by physicochemical properties, improved how much unbound compound reached the brain relative to plasma in mice.
- The resulting lead, compound 16, raised NAD+ levels in mouse brain and lung tissue in a dose-dependent manner across an oral dosing range tested in vivo.
Uncompetitive, ADPR-adduct trapping is a nice trick — you're exploiting the product complex instead of slugging it out in a crowded NAD+ pocket, which should buy clean kinetics without fighting high cellular substrate levels. Downside: SAR now rides on substrate turnover, so simple biochemical assays get harder to interpret. Covalently locking the heteroaromatic-imidazole dihedral is a solid rigidification move, but I'd want the synthetic route in hand before calling it generalizable — tethering a warhead onto a tricyclic core usually adds steps and eats yield. The real work here is the Kp,uu grind: iterative core/linker tuning to buy brain exposure without bleeding potency, textbook CNS med-chem, nothing exotic, just disciplined execution. Given CD38's broad peripheral expression, especially on immune cells, I'd want peripheral engagement/immune liability data before this goes further — daratumumab's antibody route sidesteps that entirely by staying extracellular.
Design and Exploration of a Tricyclic Series of CNS-Penetrant CD38 Small Molecule Inhibitors ↗
Siderophore 'Trojan Horse' Boosts Antibiotic Potency Against Resistant Klebsiella
- Chemists conjugated the beta-lactam antibiotic aztreonam to aerobactin, a bacterial iron-scavenging siderophore, exploiting bacteria's own iron-uptake machinery as a 'Trojan horse' to smuggle the drug inside cells.
- A modular synthetic route enabled controlled mono- and di-functionalization of aerobactin, with late-stage click-chemistry (CuAAC) attachment of payloads, providing a flexible platform applicable beyond this single conjugate.
- The lead monovalent conjugate was markedly more potent than aztreonam alone against a hypervirulent, clinically concerning Klebsiella pneumoniae strain, a substantial improvement over the parent antibiotic.
- Competition and iron-dependent activity studies confirmed delivery proceeds through the aerobactin iron-acquisition pathway, supporting genuine siderophore-mediated uptake rather than incidental potency gains.
- The results establish aerobactin as a viable scaffold for delivering antibacterial payloads against multidrug-resistant, hypervirulent Enterobacteriaceae.
Call this the cefiderocol playbook done cleaner. Aerobactin's a natural Fe(III) chelator with dedicated Klebsiella uptake receptors, so hijacking it to smuggle aztreonam past the outer membrane is exactly the kind of Trojan-horse logic that's already proven clinically viable — nice to see it extended to a hypervirulent strain, which is a genuinely scary unmet-need bug. What I like more, honestly, is the platform: modular mono-/di-functionalization plus late-stage CuAAC means this isn't a one-off heroic synthesis, it's a conjugation chassis I could point at other payloads. And they didn't just show a potency bump and wave hands — the competition/iron-dependence data actually nail down siderophore-pathway uptake, not some off-target membrane-permeabilization artifact. That's the control every conjugate paper should run but often skips.
DT-9081: Orally Bioavailable EP4 Receptor Antagonist Reaches Clinical Testing in Solid Tumors
- The EP4 receptor (EP4R), a prostaglandin E2 receptor subtype, is a promising immuno-oncology target because its signaling dampens antitumor immunity and drives tumor-associated inflammation.
- A scaffold hopping strategy moved medicinal chemists away from earlier EP4R antagonist chemotypes to a novel chemical series with improved potency and pharmacokinetics.
- Structure-activity relationship (SAR) studies then guided lead optimization, balancing target potency, selectivity, and drug-like properties.
- This process yielded DT-9081, an orally bioavailable small-molecule EP4R antagonist combining potent receptor antagonism, favorable ADME properties, and a clean preclinical safety profile.
- In vitro and in vivo pharmacology data support DT-9081's ability to modulate tumor immunity, and the compound has already completed a Phase I monotherapy trial in patients with solid cancers.
Finally, the paper behind the registry entry. Scaffold hopping off the earlier EP4 chemotypes almost certainly means they were fighting a liability — hERG, metabolic soft spot, take your pick — in the first series; jumping cores is usually the tell that a fix, not a patch, was needed. What's striking is the pace: hit-to-Phase-I told in one publication reads as a genuinely tractable SAR, not a rescue job. The harder sell is mechanism — EP4 antagonism doesn't kill tumor cells directly, it pulls the brake off PGE2-driven immune suppression, so efficacy will live or die on combination data, not monotherapy shrinkage. Worth tracking how DT-9081's selectivity stacks up against the other EP4 antagonists already in the clinic.
Direct-to-Biology Approach Delivers a Selective GRP78 Inhibitor Probe
- GRP78 (BiP/HSPA5) is a chaperone in the highly conserved HSP70 family, making isoform-selective inhibitors difficult to design.
- Using a Direct-to-Biology (D2B) strategy — synthesizing and screening compounds without intermediate purification — researchers identified compound 12 as a selective GRP78 inhibitor.
- Compound 12 binds the peptide-binding pocket in GRP78's substrate-binding domain and is selective for GRP78 over other tested HSP70 isoforms.
- It potently and selectively kills A549 lung cancer cells while showing minimal activity in other tested lung cancer cell lines.
- Cellular thermal shift assay (CETSA) confirmed cellular target engagement, and compound 12 modulates GRP78-linked unfolded protein response (UPR) stress signaling.
- The authors present compound 12 as a chemical probe for studying GRP78 biology and a starting point for GRP78-targeted therapeutics.
Substrate-binding domain, not the ATPase pocket — that's the harder but more selective play, since most HSP70-family programs chase the nucleotide site and inherit its cross-reactivity problem. Getting selectivity for GRP78 over other HSP70 isoforms out of a peptide-binding groove is a real medicinal chemistry win; those pockets are shallow and promiscuous by design. What I'd want to see next: the SAR trail from D2B — crude-plate hits jumping straight to CETSA-confirmed engagement is fast, but I'd want a clean resynthesis and dose-response before trusting potency off unpurified reactions. Still, as a probe-grade starting point with A549-selective killing, compound 12 is a legitimate template for follow-on optimization, not another ATPase-site me-too.
Development of Isoform-Selective GRP78 Inhibitors from a Direct-to-Biology Strategy ↗
Covalent Small Molecule RVJB59 Stabilizes Two Cancer-Driving p53 Mutants
- p53 is the tumor suppressor most frequently inactivated in cancer, and hotspot mutations such as R280K and R273H destabilize the folded DNA-binding domain, making mutant p53 reactivation a long-standing 'undruggable' target class.
- The study describes RVJB59, a small molecule from a tryptophanol-derived oxazoloisoindolinone series, designed to covalently engage mutant p53 protein rather than bind it only reversibly.
- Biophysical thermal-stability assays reported for this compound series show increased melting stability of mutant p53 DNA-binding domains, consistent with partial restoration of a more folded, wild-type-like conformation.
- Combining covalent engagement with thermostabilization supports a mutant-reactivation strategy aimed at restoring p53 tumor-suppressor function in cancers driven by the R280K and R273H mutations.
Mutant p53 reactivation is the target class every oncology med chemist wants a win on — most p53 lesions are destabilizing loss-of-function, not a clean druggable pocket, so 'fix the fold' beats 'block the site.' RVJB59's angle — covalent engagement plus measurable thermal stabilization of R280K and R273H DBDs — is mechanistically the right read: lock a reactive residue, nudge the folding equilibrium back toward a wild-type-like conformation. My first questions are the covalent-chemist ones: which residue, what warhead, how clean is selectivity across the proteome — thermal-shift data alone won't settle that. Worth benchmarking against PC14586/rezatapopt's reversible pocket-binding approach for R175H; different mutant, different chemotype, same underlying bet. Reads as solid hit-to-lead chemical biology, not anything near clinic-ready.