Kinases
33 articles
Cofolding models can place the ligand right while getting the protein conformation wrong
- AlphaFold3, RoseTTAFold3, Boltz-2 and Chai-1 were benchmarked on kinases and Class A GPCRs, families whose pharmacology depends on defined conformational states.
- Only complexes released after all four models' training cutoffs were used, plus one earlier control structure, to give a prospective test.
- Correct ligand placement turned out to be systematically decoupled from accurate prediction of the surrounding protein conformation.
For anyone docking into cofolded poses, this is the warning label: a plausible ligand pose does not mean the DFG state or GPCR activation state is right. That matters most for type II kinase inhibitors and biased GPCR ligands, where the conformation is the whole point. I'd treat cofolded structures as hypotheses to validate against known conformational markers before using them for SAR design.
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.
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.
Kinase inhibitors often change protonation or tautomer state on binding, MCCE modelling shows
- Multi-conformation continuum electrostatics was applied to 37 co-crystal structures of nine kinase domains with 18 approved inhibitors.
- Protein net charge stayed largely stable on binding, whereas inhibitor charge states frequently shifted up or down.
- Binding can resolve two near-equal solution tautomers into one, creating free-energy differences of a few kcal/mol.
Docking with one fixed protonation state is quietly baked into most of our virtual screening, and this says it can be wrong by kcal/mol for approved drugs. When a scaffold with a tautomerisable heterocycle misbehaves in SAR, I'd now check its bound-state tautomer before blaming the pocket.
Kinase Inhibitors can Change Protonation or Tautomeric State upon Binding ↗
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 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 ↗
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.
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.
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.
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.
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.
ArriVent's first-line EGFR exon 20 NSCLC phase 3 misses its primary endpoint
- Fierce Biotech reports that ArriVent's phase 3 FURVENT trial of the EGFR inhibitor firmonertinib missed its primary progression-free survival endpoint by blinded central review in first-line EGFR exon 20 insertion NSCLC.
- The higher dose showed only a modest numerical edge over platinum chemotherapy and the lower dose did numerically worse, while investigator-assessed results looked more favorable.
- ArriVent's shares fell sharply on the news.
A small central-review margin over chemo, in a setting where J&J's Rybrevant-plus-chemo regimen has already set a higher bar, leaves firmonertinib hard to position in exon 20. The investigator-versus-central gap gives ArriVent a regulatory conversation but a thin commercial story. The PACC-mutation ALPACCA study now looks like the company's real value driver.
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.
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.
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 ↗
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 ↗
FDA approves Lilly's Jaypirca for previously untreated CLL and SLL
- The FDA approved Jaypirca (pirtobrutinib) for previously untreated chronic lymphocytic leukemia and small lymphocytic lymphoma.
- It moves the non-covalent BTK inhibitor from later-line use into the first-line setting.
First-line is where the BTK market's volume sits, so this is the label that matters commercially. It puts a non-covalent inhibitor directly against the covalent incumbents, where it competes on tolerability and on not depending on the Cys481 bond. Watch how payers and guidelines place it relative to fixed-duration venetoclax regimens.
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 ↗
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.
Maruho and BMS Partner on Japan Sales for TYK2 Inhibitor Sotyktu
- Maruho and Bristol Myers Squibb (BMS) signed a Japan sales partnership for Sotyktu (deucravacitinib), BMS's oral TYK2 inhibitor, starting October 1, 2026.
- Maruho will handle domestic sales and distribution, promoting the drug in dermatology and rheumatology, while BMS continues promotion in rheumatology.
- Sotyktu is approved for plaque, pustular and erythrodermic psoriasis, with a psoriatic arthritis indication added in May 2026.
BMS ceding Japan commercial lead to Maruho is a tacit admission that dermatologist relationships beat global scale here — the classic foreign-innovator/domestic-specialist access play. Adding rheumatology promotion right after the May PsA nod signals urgency to outrun oral JAK rivals before positioning hardens. For Maruho, it's low-risk topline padding that fits its derm book without R&D exposure.
Aminopyrazole Lead Optimization Yields Selective PLK4 Inhibitor EXEL-1855
- Exelixis researchers optimized an aminopyrazole hit series targeting PLK4, a kinase essential for centriole duplication, culminating in the advanced compound EXEL-1855.
- Structure-guided SAR and selectivity profiling addressed off-target kinase liabilities that had limited earlier aminopyrazole PLK4 inhibitors such as centrinone.
- In preclinical tumor models, EXEL-1855 showed strong antitumor activity, supporting its selection as a development candidate.
Selectivity was always the aminopyrazole scaffold's weak spot — centrinone's off-target kinase hits (PLK1/2/3, Aurora) made it a great chemical probe but a poor drug candidate. Getting EXEL-1855 to "development candidate" with a clean kinome profile is the real milestone here, not the potency number. PLK4's centrosome-duplication mechanism is also refreshingly uncrowded real estate next to the CDK/Aurora pileup.
Imidazole Scaffold Swap Delivers Selective, Oral CDK2 Inhibitor INCB127443
- An earlier pyrazole-based CDK2 inhibitor scaffold was computationally redesigned around an imidazole core to improve selectivity over CDK1.
- The new chemotype was optimized simultaneously for potency, CDK1/CDK2 selectivity, and physicochemical properties.
- This work yielded INCB127443, an orally bioavailable candidate with favorable CDK1 selectivity and a flat pharmacokinetic profile enabling sustained in vivo target coverage.
Swapping pyrazole for imidazole to fix CDK1 selectivity is a single-atom-position bet—when it works, it usually means the selectivity handle is a subtle H-bond vector difference in the near-identical ATP pockets, not a size mismatch, which is the harder kind to exploit on purpose. Imidazole is cheap, well-trodden SAR territory, and the flat PK is the real prize for sustained target coverage.
Discovery of INCB127443: A Potent and Orally Available Inhibitor of Cyclin-Dependent Kinase 2 ↗
Tuning Brain Penetration in DYRK1A Inhibitors for Alzheimer's Neuroinflammation
- Builds on a prior azaindole-quinazoline lead compound and addresses its limited blood-brain barrier penetration.
- Uses an intramolecular cyclization strategy to mask a hydrogen-bond-donating amine group that was prone to P-glycoprotein-mediated efflux.
- Resulting analogs retain strong DYRK1A inhibitory activity while markedly improving brain exposure.
- Optimized compounds reduce microglia-driven neuroinflammatory markers in disease-relevant models.
Masking an H-bond donor by intramolecular cyclization to dodge P-gp is a well-worn CNS trick, but pulling it off on an azaindole-quinazoline kinase core without bleeding DYRK1A potency is the part most efflux-liability campaigns fail at. If the microglial neuroinflammation readout replicates in a second model, this is a genuinely reusable template for other P-gp-limited kinase programs.
New CK1δ-Targeting Degraders Curb NRAS-Mutant Melanoma Growth
- Building on prior work identifying CK1δ as an upstream stabilizer of oncogenic NRAS, the team developed small-molecule degraders that trigger CK1δ's proteasomal breakdown.
- Chemical optimization focused on achieving selectivity for CK1δ over its close paralogs CK1α and CK1ε, which share highly similar kinase domains.
- Iterative structure-activity relationship analysis across a synthesized compound series balanced degradation potency, isoform selectivity, and cellular activity.
- Degrading CK1δ removed its support for oncogenic NRAS protein stability, lowering NRAS levels and dampening downstream signaling in melanoma cells.
- In NRAS-mutant melanoma cell models, the optimized degraders suppressed proliferation, positioning CK1δ degradation as a potential strategy for an otherwise hard-to-drug oncogenic driver.
CK1δ/α/ε selectivity is the real fight here — those kinase domains are similar enough that classic ATP-competitive chemistry rarely holds up cleanly; if they're threading that needle with a degrader, ternary-complex geometry, not just binary affinity, is probably doing the selectivity work, which is the whole pitch for going bifunctional over yet another inhibitor. Smart use of event-driven pharmacology to reach something genuinely undruggable — NRAS has no covalent handle like G12C, so knocking down an upstream stabilizer is a legitimate end-run, not a gimmick. Still want to see the actual chemotype and E3 handle before getting excited — 'synthesized series, iterative SAR' tells me nothing about scaffold novelty or synthetic cost, and degrading a kinase with this many substrates makes me nervous about toxicity beyond the CK1α story. If selectivity and PK hold up in vivo, this is a template worth stealing for other 'stabilizer' targets propping up undruggable oncoproteins.
GSK licenses HUTCHMED's first-in-class KRAS-EGFR conjugate HMPL-A830 in deal worth up to $1.3B
- HUTCHMED and a GSK subsidiary signed an exclusive development and license agreement for HMPL-A830, described as a first-in-class KRAS-EGFR Antibody-Targeted Therapy Conjugate (ATTC).
- HMPL-A830 pairs a highly selective, potent small-molecule KRAS inhibitor payload with an anti-EGFR antibody, delivering the inhibitor selectively to EGFR-expressing tumor cells while also blocking EGFR signaling.
- GSK gains worldwide development and commercialization rights excluding Mainland China, Hong Kong, Macau and Taiwan, which HUTCHMED retains.
- Deal terms: $110 million upfront, up to $1.295 billion in additional development, regulatory and commercial milestone payments, plus tiered royalties on net sales.
- HUTCHMED will conduct the global Phase 1 program, expected to start in H2 2026, after which GSK takes over subsequent clinical development and commercialization.
- Initial clinical development will focus on colorectal, pancreatic and lung cancers.
Another Western major fills its oncology pipeline via China-origination rather than in-house discovery — GSK joins a fast-growing queue of ADC/conjugate deals mining HUTCHMED's pipeline for de-risked-but-early assets. The math is telling: $110M upfront against a $1.295B ceiling is roughly 8.5% at signing — real conviction, heavily hedged, standard for a preclinical/Phase 1 asset where GSK is paying mostly for optionality until clinical data lands. The ATTC design — a small-molecule KRAS payload riding an EGFR antibody — is a genuinely differentiated angle in an overcrowded KRAS field, avoiding classic cytotoxic-ADC toxicity while adding tumor-selective targeting. And HUTCHMED keeping Greater China rights again signals its now-familiar playbook: license out ex-China, retain commercial control at home.
GSK to license Hutchmed's KRAS-EGFR cancer drug for $110M upfront ↗
Wild-Type-Sparing PI3Kα H1047R Inhibitors Identified from Quinazolinone Series
- Approved PI3Kα inhibitors for HR+/HER2− PIK3CA-mutated breast cancer cause dose-limiting hyperglycemia and other adverse effects linked to inhibition of wild-type PI3Kα.
- Researchers designed a series of tetrasubstituted quinazolin-4(3H)-one compounds intended to selectively inhibit the oncogenic PI3Kα H1047R mutant.
- Selectivity for the mutant enzyme over wild-type PI3Kα is proposed to stem from a slow-on, slow-off binding mechanism.
- Lead compound 34 showed potent, mutant-selective activity in vitro along with a favorable ADME profile.
- In a T47D xenograft mouse model, compound 34 produced significant tumor growth inhibition without affecting blood glucose or serum insulin levels, unlike a benchmark approved PI3Kα inhibitor.
- The authors note that further optimization of compound 34 is needed to lower the efficacious dose and improve tolerability.
Alpelisib's hyperglycemia problem is the elephant in every PI3Kα SAR discussion — it's the reason dose reductions dog that drug in clinic, tracing straight back to wild-type inhibition in normal insulin signaling. A slow-on, slow-off kinetic selectivity mechanism here is more interesting than a static pocket-shape argument: if H1047R's altered conformational dynamics let this quinazolinone linger on mutant enzyme while it washes out of WT, that's a residence-time story I'd want kinITC and washout kinetics to confirm before fully believing. Tetrasubstituted quinazolinones aren't an exotic scaffold to make, which helps for a program needing heavy analoging around that pocket. Clean xenograft efficacy without glucose/insulin perturbation is the proof-of-concept that matters — but the authors' own admission that compound 34 needs a lower efficacious dose and better tolerability is the real tell: promising probe, not yet a candidate.
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.
Antibody-Guided PROTAC Conjugate Blocks Tumor-Stroma Crosstalk by Silencing Extracellular Vesicles
- Researchers built Ctx-ETAC, a degrader-antibody conjugate pairing the approved EGFR antibody cetuximab with an engineered PROTAC payload, attached via a bioorthogonal reaction at a defined, controlled ratio per antibody.
- Its PROTAC payload pairs an indomethacin-derived COX-2 ligand with a VHL-recruiting peptide via a cathepsin B-cleavable linker, releasing the degrader selectively inside EGFR-positive tumor cells and activated fibroblasts.
- Degrading COX-2 in both cell types substantially curtails extracellular vesicle secretion, severing a key tumor-stroma signaling channel and nudging fibroblasts toward a quiescent, less tumor-supportive state.
- In a lung cancer xenograft model, Ctx-ETAC outperformed cetuximab alone in restraining tumor growth without added systemic toxicity, supporting microenvironment-targeted degradation as a therapeutic strategy.
Finally, a DAC that isn't just "ADC with a cooler payload" — swapping a cytotoxin for a VHL-PROTAC means efficacy doesn't hinge on brute-force poisoning of every internalized antibody; you get catalytic, event-driven target destruction instead. Smart target choice: COX-2 isn't the oncogenic driver, it's stromal plumbing. Cutting EV secretion to defuse tumor-fibroblast crosstalk instead of chasing EGFR resistance mutations directly is a genuinely different SAR logic than the usual "degrade the driver" playbook. Chemistry-wise, nothing exotic — indomethacin-COX-2 ligand, VHL peptide, cathepsin B-cleavable linker, defined-DAR bioorthogonal attachment. That's the point: boringly tractable, which is exactly what a translatable conjugation platform should look like. Real question is whether COX-2/EV silencing holds up in a fibroblast-rich, resistant tumor, not just a clean xenograft — but as a proof that microenvironment-directed degradation is maturing past a concept, this is convincing.
Structural Survey Reveals How Kinase Inhibitors Engage Conserved Catalytic Residues
- More than 300 X-ray cocrystal structures spanning diverse kinase-inhibitor complexes were analyzed to catalog recurring non-covalent contact patterns.
- The study highlights a set of conserved Lys, Asp, and Glu residues near the ATP pocket, dubbed "Catalytic Cluster Residues" (CCRs), that support catalysis and frequently contact bound inhibitors.
- Across most inhibitor chemotypes, these polar residues form non-covalent interactions rather than covalent bonds, making them broadly relevant handles for ligand design.
- Side-chain orientation of the CCRs tracks with the kinase's active or inactive conformational state, linking binding geometry to structural dynamics.
- The authors argue this conformation-coupled behavior can guide rational, structure-based inhibitor design aimed at improving potency and tuning selectivity across the kinome.
"Catalytic Cluster Residues" is new branding for something most kinase chemists already lean on informally — the Lys-Glu ion pair, DFG-Asp contacts. The real value here is systematizing it: 300+ structures gives a statistical backbone for deciding when to actually chase these polar contacts instead of hinge binding or a back-pocket selectivity vector. If CCR geometry really tracks active/inactive state, that's a usable lever — bias type-I vs type-II engagement via salt bridges and H-bonds instead of reaching for a covalent warhead, attractive when cysteine liabilities or covalent reversibility are a concern. I'm skeptical the conformational-coupling claim generalizes cleanly across the kinome, though — 300 structures sounds like a lot until you split it by subfamily, and PDB deposition bias means scaffolds like EGFR, ABL, and CDKs are almost certainly overrepresented relative to understudied kinases.
A Structural Perspective on Non-covalent Targeting of Conserved Polar Residues in Protein Kinases ↗