DMPK & ADME
24 articles
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.
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.
Fragment-synergy genetic algorithm turns P-gp substrates into non-substrates
- P-gp efflux limits bioavailability and CNS exposure, and ML substrate classifiers rarely translate into concrete design moves.
- SF-GA builds fragment synergy analysis into the mutation step of a genetic algorithm, biasing replacements toward substructures that co-occur in non-substrates.
- Against GA and reinforcement-learning baselines at a fixed evaluation budget it was competitive and gave the most synthetically accessible molecules, reporting the removed and inserted fragments for every accepted mutation.
The part I would use is the per-mutation fragment report: it reads like a matched-pair suggestion list, which is how a chemist actually wants a model to talk. Competitive rather than better optimization performance means the value is interpretability and synthesizability, not raw efficiency. Prospective validation on real efflux assays is the missing piece.
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.
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 ↗
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 ↗
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 ↗
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.
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.
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.
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.
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.
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.
Study Probes the Chemical Basis of Cell-Penetrating Poly(disulfide) Uptake
- Poly(disulfide)s are dynamic-covalent polymers whose guanidinium-rich chains cross cell membranes via thiol-mediated uptake, engaging surface thiols rather than classical endocytosis.
- This study probes the chemical basis of that uptake, linking polymer structure and disulfide exchange to membrane translocation and cytosolic release.
- It reinforces poly(disulfide)s as a macromolecular delivery modality for proteins, antibodies, and nucleic acids, bypassing lysosomal degradation.
Skipping endocytosis entirely is the real prize: LNPs and most CPPs still have to escape an endosome, and that's where most of your payload dies. A dynamic-covalent scaffold means guanidinium density and disulfide exchange rate are dial-in knobs, not a peptide sequence you're stuck re-screening. Worth revisiting for antibody or siRNA payloads where endosomal escape is currently the bottleneck.
Brain-Penetrant Covalent BChE Inhibitor Shows Procognitive Effects in Alzheimer's Model
- Researchers used structure-guided design to develop a covalent small-molecule inhibitor of human butyrylcholinesterase (BChE), an enzyme increasingly implicated in Alzheimer's disease progression.
- The lead compound was engineered for blood-brain barrier penetration, a key hurdle for centrally acting cholinesterase inhibitors.
- In vivo testing showed procognitive efficacy, supporting covalent BChE inhibition as a potential treatment approach for Alzheimer's disease.
BChE rising while AChE falls late in disease is finally moving the field past AChE-centric dogma. A covalent warhead in a serine hydrolase family full of close paralogs (AChE, esterases) needs hard selectivity data, not just potency. What actually differentiates this from rivastigmine-class reversible inhibitors is CNS penetration — brain exposure they never solved well.
Fluorine Tweaks to Lipid Nanoparticles Boost PROTAC Delivery Efficiency
- Researchers built ionizable lipid nanoparticles with fluorinated lipid tails to encapsulate and deliver a PROTAC degrader payload.
- Tuning the degree of fluorination altered nanoparticle physicochemical properties and redirected intracellular trafficking, promoting more efficient endosomal escape into the cytosol.
- Optimized fluorinated formulations achieved greater cytosolic PROTAC release and stronger target-protein degradation than non-fluorinated lipid controls.
Most LNP-delivered PROTAC payload never escapes the endosome — it gets trapped and degraded lysosomally, so tuning fluorine content on the lipid tail to boost cytosolic release is a smart lever, borrowed straight from siRNA-LNP playbooks. If this scaffold generalizes beyond whichever degrader they tested, it could rescue plenty of otherwise-undruggable bifunctional PROTACs too big or polar for oral dosing.
Oral PROTAC Degrader Targets STAT6 in Atopic Dermatitis
- A new PROTAC degrader targets STAT6, the transcription factor that carries IL-4/IL-13 signals driving Th2-type allergic inflammation.
- Instead of inhibiting STAT6, the molecule links a STAT6-binding fragment to a degradation handle for potency and selectivity over related STAT proteins.
- It reportedly showed oral efficacy in preclinical models, pointing to a pill-based alternative to injectable biologics for atopic dermatitis.
Oral bioavailability is the harder win here than target choice — PROTACs routinely blow past Lipinski/bRo5 limits (MW, PSA), so a gut-stable, orally efficacious degrader is the rarer synthetic feat. If STAT1/3/5 selectivity holds up in vivo, this leapfrogs injectable dupilumab and pressures other oral STAT6 degrader programs already in the clinic.
New Computational Score Aims to Predict PROTAC Oral Absorption
- PROTACs (proteolysis-targeting chimeras) are large, polar, conformationally flexible molecules that fall outside classical Rule-of-5 space, making oral absorption difficult to predict from standard physicochemical filters alone.
- The paper introduces a fully computational scoring approach for oral absorption, intended to support rational, in silico PROTAC design earlier in the discovery process rather than relying mainly on measured properties.
- The score is built from computed molecular descriptors likely spanning size, polarity/lipophilicity balance, flexibility, and conformational behavior such as intramolecular folding — features previously linked to permeability in beyond-Rule-of-5 compounds.
- By combining these descriptors into a single predictive metric, the method aims to help chemists rank or triage PROTAC candidates for oral-absorption potential before synthesis.
- The authors position the score as a practical design-stage tool for guiding linker, warhead, and E3-ligand modifications toward improved oral bioavailability, complementing rather than replacing experimental permeability assays.
Any tool that lets me deprioritize a bad linker before I burn two weeks on synthesis and a Caco-2 run is welcome — PROTAC medchem cycles are brutal, and "just make it and test permeability" stops being an option once your library is 50+ analogs deep. That said, I've seen enough beyond-Ro5 permeability models oversell intramolecular H-bonding and chameleonic folding to stay skeptical until I see the validation set and how it handles my actual chemotypes — conformational behavior is exactly the thing computation still fakes worst. Where this actually helps is triage, not truth: rank candidates, flag the obvious dead-on-arrivals, then spend the wet-lab budget on the borderline cases. That's a real upgrade over eyeballing MW/PSA/cLogP cutoffs, which everyone in the PROTAC space already knows don't apply. If the descriptors genuinely capture folding propensity rather than just correlating with size, this could meaningfully shift where we spend linker SAR effort.
New Benzimidazole-Tetrahydrofuran Series Delivers Potent, Selective NaV1.8 Inhibitor Lead for Pain
- NaV1.8 inhibition is a clinically validated non-opioid strategy for pain, with the marketed drug VX-548 (Journavx) serving as the benchmark; its metabolic pathways in humans and rats are well characterized.
- Researchers designed a new chemotype, 2-(2-benzimidazole)-substituted tetrahydrofurans, and applied structure-based optimization to circumvent VX-548's known metabolic liabilities while retaining nanomolar NaV1.8 potency and subtype selectivity.
- The resulting lead, compound 31, showed favorable oral bioavailability in rats, with plasma AUC more than 10-fold higher than VX-548, alongside potent in vivo analgesic efficacy.
- Pharmacokinetic behavior was consistent across species, with favorable profiles also seen in beagle dogs and cynomolgus monkeys.
- Compound 31 exhibited a favorable early safety profile, including no genotoxicity and weak hERG inhibition, supporting its status as a metabolically optimized preclinical lead for further evaluation.
Call this a metabolism play more than a new-target story. With VX-548's clearance liabilities already mapped in human and rat, swapping to a 2-benzimidazole-tetrahydrofuran scaffold reads as targeted scaffold-hopping around known soft spots rather than blind SAR exploration. That's the efficient way to run a fast-follower program: let the first approved drug's ADME data write your design brief. A >10x jump in rat AUC is the number that matters here — that's the difference between a compound needing frequent dosing with exposure gaps and one you can actually push into efficacy studies with margin. Clean hERG and no genotox flags this early derisks the biggest attrition risks before you've spent tox budget. The THF-benzimidazole core isn't exotic chemistry, nothing hard to scale — this looks like a real backup/second-gen candidate, not just a paper compound.
Novel VHL-Recruiting PROTACs Degrade Mutant EGFR and Show Efficacy in NSCLC Models
- Researchers designed VHL-recruiting PROTAC degraders targeting EGFR, aiming to overcome acquired resistance to conventional EGFR kinase inhibitors in non-small cell lung cancer (NSCLC).
- Lead compounds C4 and D4 achieved potent, selective, and durable degradation of the EGFR Del19 and L858R resistance mutants.
- C4 induced cell cycle arrest and apoptosis, showed subnanomolar antiproliferative activity, and produced significant tumor regression in an HCC827 xenograft model at low intravenous doses on a reduced twice-weekly schedule.
- D4 was orally bioavailable and blood-brain barrier penetrant, and oral dosing completely halted tumor growth in vivo.
- The findings support a degradation-based strategy, rather than conventional inhibition, as a route to next-generation EGFR-directed therapies with potential central nervous system relevance.
D4 clearing both the oral bioavailability and blood-brain-barrier bars is the real headline here, more than the VHL-EGFR chemistry itself — most VHL degraders are 800-1000 Da PEG-linked bricks, gorgeous in a dish, DOA as an oral CNS drug. That's the developability wall this class has been stuck at. C4's profile reads more like a conventional IV PROTAC: subnanomolar antiproliferative potency and regression at low twice-weekly doses is a solid therapeutic index, but the reduced dosing schedule signals they're still managing catalytic turnover and clearance, not solving it outright. Degrading Del19/L858R instead of inhibiting them sidesteps the secondary-mutation resistance that keeps eroding osimertinib responses. If selectivity holds against WT EGFR in vivo, this is a real next-gen chemotype for NSCLC, not just a mechanistic proof-of-concept.
Researchers Advance Quinoline CYP8B1 Inhibitor as Lead for Metabolic Disease
- CYP8B1 is a liver enzyme in the bile-acid synthesis pathway now being explored as a drug target for metabolic disorders such as nonalcoholic fatty liver disease and type 2 diabetes.
- The project started from compound 1, a CYP8B1 inhibitor identified by high-throughput screening, which broke down too quickly to be tested in live animals.
- Chemists used structure-based design and metabolite identification to learn how the molecule degraded, then ran DMPK-guided analog synthesis to explore structure-activity relationships.
- That work produced compound 9, a quinoline analog with markedly improved metabolic stability.
- In mice, compound 9 showed robust in vivo CYP8B1 inhibition, providing a validated lead for further optimization.
This is textbook DMPK-guided lead optimization done right: compound 1 degrades too fast for in vivo work, so instead of abandoning it, they identify the metabolite, figure out exactly where the molecule is falling apart, and redesign around that liability. That's the disciplined way to do hit-to-lead, and it's refreshing to see it laid out explicitly rather than glossed over. Landing on a quinoline is a plus for tractability — cheap chemistry, well-understood SAR space, easy to riff on for follow-up analogs. CYP8B1/bile-acid signaling is also a nice change of scenery from the overworked FXR and GLP-1 real estate in NAFLD/T2D. My one nagging question: going from compound 1 to a stable, in vivo-active compound 9 reads suspiciously clean for a single campaign — what substituent or ring modification actually killed the metabolic soft spot? That's the detail I'd want in the SAR table before believing this fully.
BBB-Crossing PROTAC Macrocycles Selectively Degrade DAPK1 in Aging Alzheimer's Brains
- BmTACs — a new class of brain-penetrant degrader molecules — fuse a macrocyclic peptide shuttle to a PROTAC-type small-molecule module.
- The peptide shuttle exploits a transcytosis route across brain blood vessels that becomes more active with age, enabling efficient blood-brain-barrier crossing and neuronal delivery.
- A chemical cage on the degrader's VHL-recruiting ligand keeps it silent until it meets the high-oxidative-stress conditions found in Alzheimer's-affected tissue, limiting activity elsewhere in the brain.
- Once activated, the compound selectively degrades an activated, disease-linked form of the kinase DAPK1.
- In aged Alzheimer's-model mice, systemic treatment reduced activated DAPK1, lessened amyloid-beta and tau pathology, and improved cognitive function, demonstrating an aging-adapted strategy for brain-targeted protein degradation.
The caged VHL ligand is the clever bit — redox-triggered decaging means the warhead sits as a prodrug until it hits oxidative-stress tissue, which could finally address the peripheral-toxicity problem that's dogged systemic PROTAC dosing. I want the counter-screen though: how much decaging leaks in non-lesion CNS tissue over chronic dosing, and does 'activated DAPK1' selectivity hold in human proteoform or is that mouse-conformer-specific? The macrocyclic peptide-small molecule hybrid is a brutal synthesis — SPPS, macrocyclization, PROTAC conjugation, yield bleeding at every step — this is proof-of-concept, not a scalable series. Exploiting age-upregulated transcytosis instead of fixed RMT receptors (transferrin, insulin) is the real advance over TfR-shuttle degraders; the open question is whether that route is druggable across disease stages, not just aged models.
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 ↗
TRI-611: A Brain-Penetrant Molecular Glue Takes Aim at ALK-Driven Lung Cancer
- TRI-611 is an orally dosed molecular glue degrader designed to eliminate ALK fusion proteins that drive a subset of non-small cell lung cancers.
- Rather than blocking ALK's active site like conventional inhibitors, it recruits the E3 ligase adaptor cereblon to a distinct surface on ALK, forming a complex that tags the protein for degradation.
- The molecule is reported to be highly selective, sparing other cereblon-dependent targets and unrelated kinases, and it degrades both wild-type and kinase-inhibitor-resistant ALK fusion variants.
- A central finding is brain penetrance: TRI-611 produced tumor regressions in intracranial as well as subcutaneous models, addressing CNS metastases that limit many existing ALK-targeted therapies.
- Degradation was rapid and long-lasting, and combining TRI-611 with standard ALK inhibitors produced more durable responses in preclinical models.
TRI-611 recruiting cereblon to a distinct, non-canonical surface on ALK — rather than working off the usual IMiD-derived degron — is the real chemistry story here; if that ternary interface holds up, it's a fresh template for kinases that don't glue easily. Wiping out kinase-inhibitor-resistant fusion variants is the killer selling point: degradation doesn't care about the affinity losses that gatekeeper/compound mutations inflict on ATP-competitive binders, so a mutant that's dead to a TKI can still form a productive ternary complex. Getting CNS exposure out of a CRBN glue is the harder chemical win — these scaffolds usually sit well outside Ro5, so brain penetrance without sacrificing ternary complex cooperativity argues for real optimization, not luck. Selectivity over other CRBN neosubstrates plus the TKI-combo data suggest this could slot in alongside inhibitors rather than just after them.
TRI-611, a selective, brain-penetrant molecular glue degrader of ALK ↗