Eight science items today: an HDAC11 inhibitor for NSCLC, TTBK1/2 probes, brain-penetrant EGFR TKI structures, an oral MRGPRX2 antagonist, allosteric covalent cereblon inhibition, a RhoJ pocket, and two Science Translational Medicine papers (TREM2 agonist, PP2A glue). Business: AstraZeneca–insitro, Merck–Moderna and RevMed's EU nod.
2026-10-16 · ⚗️MRGPRX2 (GPCR) · ACS Medicinal Chemistry Letters (ACS)
- 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.
💡 PointsScoring 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 ↗
2026-10-16 · ⚗️RhoJ (Rho GTPase) · bioRxiv
- 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.
💡 PointsUsing 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 ↗
2026-10-15 · ⚗️EGFR (kinase) · ACS Medicinal Chemistry Letters (ACS)
- 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.
💡 PointsCNS 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 ↗
2026-10-15 · ⚗️Cereblon (E3 ligase) · bioRxiv
- 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'.
💡 PointsEvery 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 ↗
2026-10-15 · ⚗️HDAC11 · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsHydroxamates 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.
Development of a Potent and Isoform-Selective HDAC11 Inhibitor with Anti-Tumor Efficacy against Non-Small Cell Lung Cancer ↗
2026-10-15 · ⚗️TTBK1/TTBK2 (kinases) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsWhat 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 · 🏢Regulatory milestone · STAT News · Revolution Medicines
- Following FDA approval, European regulators have recommended approval of Revolution Medicines' Rasonque (daraxonrasib) for pancreatic cancer, per STAT+.
- The recommendation moves the RAS(ON) inhibitor toward a second major market.
- This summary rests on the article's teaser; a separate search could not confirm the EU opinion.
💡 PointsIf confirmed, a quick EU follow-on after the US nod shows how fast an oral RAS(ON) inhibitor with a clear survival benefit in a deadly cancer can move. For analysts the questions now shift to pricing, reimbursement and label expansion beyond second-line pancreatic disease. It also validates the tri-complex approach for peers still chasing KRAS in the same tumor type.
STAT+: RevMed's pancreatic cancer drug nears European approval ↗
2026-10-15 · 🏢Research collaboration · Fierce Biotech · AstraZeneca / insitro
- AstraZeneca and insitro signed a collaboration to find novel drug targets for liver and heart diseases using AI.
- Reported terms: a modest upfront payment of $40 million, with milestones taking the total to about $1.5 billion.
- Terms come from search-snippet reporting of the Fierce Biotech article, which could not be opened directly.
💡 PointsA small upfront against a large biobucks headline is the standard shape for platform-style target discovery: AstraZeneca pays for optionality, not assets. The partner choice shows where AZ sees the pharmacology bottleneck, in picking targets rather than designing molecules. I'd read it as another hedge alongside its other AI deals; the payoff comes only if the targets are credible.
AstraZeneca inks $1.5B insitro deal for AI-enabled target discovery of liver, heart disease drugs ↗
2026-10-15 · 🏢Pipeline progress · STAT News · Merck / Moderna
- At the STAT Summit, Moderna's Stephen Hoge and Merck's Dean Li discussed pairing Keytruda with personalized mRNA cancer vaccines.
- Both executives framed the first positive results as a start, with much left to work out.
- This summary rests on the article's teaser, not the full text.
💡 PointsPairing a personalized vaccine with Keytruda protects Merck's franchise as PD-1 exclusivity ages, so Merck has a strategic reason beyond the science. The executives' caution about what comes next is telling: the open questions are tumor types, dosing settings and manufacturing scale. Rivals with other neoantigen approaches should read it as a bar to clear.
Merck and Moderna have 'lot of exploring to do' after initial cancer vaccine success ↗