Six science items, from gut-restricted RXFP4 agonists and covalent GBA2 inhibitors to cereblon PROTAC prodrugs and an open DNA glycosylase screen, plus four deals and setbacks: Novo–Hengrui, AstraZeneca–Summit, Roche's emugrobart exit and Merck's Recarbrio withdrawal.
2026-09-29 · ⚗️Carbonic anhydrase IX inhibitor (sulfamate) · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsCA 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 ↗
2026-09-29 · ⚗️GBA2 covalent inhibitor (cyclitol aziridine) · Journal of the American Chemical Society (ACS)
- 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.
💡 PointsTurning 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.
β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors ↗
2026-09-29 · ⚗️RXFP4 (GPCR) agonist · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsGetting 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.
Structure-Guided Discovery of Highly Selective, Gut-Restricted RXFP4 Agonists for the Treatment of Constipation ↗
2026-09-28 · ⚗️Covalent lysine-directed chemoproteomic probe · bioRxiv
- 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.
💡 PointsCovalent 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.
Natural product-derived azaphilones are selective scaffolds for covalent lysine liganding in live cells ↗
2026-09-28 · ⚗️Targeted protein degradation (cereblon PROTAC prodrugs) · Angewandte Chemie International Edition (Wiley)
- 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.
💡 PointsThe 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 ↗
2026-09-28 · ⚗️DNA glycosylases (HTS, chemogenomic library) · bioRxiv
- 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.
💡 PointsGlycosylases 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 ↗
2026-09-29 · 🏢licensing deal · Endpoints News · Novo Nordisk / Jiangsu Hengrui Pharmaceuticals
- Novo gets exclusive rights outside mainland China, Hong Kong, Macau and Taiwan to HRS-1596, a once-weekly oral GLP-1/GIP dual agonist, for $300M upfront and up to $2.3B in milestones plus royalties.
- The asset is Phase 1-ready, with Chinese clearance to start trials in weight management and type 2 diabetes; closing is expected in Q4 2026.
💡 PointsPaying $300M upfront for a molecule that hasn't dosed a human outside China shows how badly Novo wants an oral follow-on while Lilly presses its lead. It also fits a pattern of buying de-risked-enough optionality from outside rather than building it, after smaller deals like Nanexa. Weekly oral bioavailability is the real technical risk, and the milestone-heavy structure shields Novo if it fails.
Novo to spend $300M upfront to license Hengrui's weekly oral weight loss drug ↗
2026-09-28 · 🏢equity investment / clinical collaboration · Fierce Biotech · AstraZeneca / Summit Therapeutics
- AstraZeneca is buying $2B of convertible preferred stock, giving it about 12% of Summit's common stock (about 10.6% fully diluted).
- The first combination pairs Summit's PD-1xVEGF bispecific ivonescimab with AstraZeneca's CLDN18.2-directed ADC in gastrointestinal cancers; a memorandum of understanding covers a broader program with more AstraZeneca ADCs.
💡 PointsThis is AstraZeneca buying a seat rather than a pipeline: equity plus combination rights instead of an acquisition or license, keeping it close to a PD-1xVEGF class it doesn't own without paying for the asset outright. The bet is that ADC plus PD-1xVEGF combinations become a next oncology backbone, with AstraZeneca's ADC portfolio as the partner of choice. The broader MOU is non-binding, so definitive terms are the thing to watch.
AstraZeneca scales Summit's PD-1xVEGF strategy with $2B investment to fuel ADC combinations ↗
2026-09-28 · 🏢product discontinuation · STAT News · Merck
- Merck is discontinuing Recarbrio, its reserve-use antibiotic combination, in the U.S. as part of a portfolio review, and says the move is unrelated to safety or quality.
- Approved seven years ago for hospital-acquired pneumonia and complicated urinary and abdominal infections with few options, it leaves Merck with only mature antibiotics and, per trade reports, no antibacterial programs in Phase II or later.
💡 PointsReserve antibiotics are meant to be used sparingly, which caps sales, and a big pharma walking away from one confirms the broken economics of anti-infective launches. Small biotechs will read this as a warning, and policymakers will cite it in the case for pull incentives. The open question is whether Merck out-licenses the product or simply sunsets it.
Merck discontinues a crucial antibiotic despite concerns over superbug resistance ↗
2026-09-28 · 🏢discontinuation · Fierce Biotech · Roche / Chugai Pharmaceutical
- Roche ended obesity development of emugrobart (GYM329), an anti-latent-myostatin sweeping antibody meant to preserve muscle alongside GLP-1 therapy, after a Phase 2 GYMINDA interim analysis made meaningful weight loss unlikely.
- Rights revert to Chugai, which is preparing to resume development in spinal muscular atrophy and is open to out-licensing; the antibody had already missed in SMA and FSHD trials in March.
💡 PointsThis dents the muscle-preservation thesis in obesity: the pitch was that myostatin blockade adds lean-mass benefit on top of incretins, and this antibody didn't deliver. Other myostatin and activin-pathway programs will face sharper partner questions about what retained lean mass means clinically. A rights return usually signals a deprioritized asset, and a Phase 3 in SMA after an earlier SMA miss looks like a long shot.
Roche drops muscle-sparing obesity antibody after flunked interim analysis ↗