Five science items today, from GPCR-degrading bispecifics and a CD73 inhibitor to soft-drug design, a new docking potential and PROTAC linker scoring, plus two obesity and macrocycle business items: Boehringer/Zealand's survodutide and Novo's Orbis deal.
2026-10-02 · ⚗️CD73 (ecto-5′-nucleotidase) inhibitor · Journal of Medicinal Chemistry (ACS)
- 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.
💡 PointsNon-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.
Discovery of LB10, a Potent and Orally Bioavailable Inhibitor of Ecto-5′-Nucleotidase as a Single Agent or in Combination for the Treatment of Lung Cancer ↗
2026-10-01 · ⚗️PROTACs (VHL-recruiting SHP2 degraders) · chemRxiv
- Linker optimization in targeted protein degradation is still largely empirical.
- The preprint asks whether current computational methods can rank close linker analogues before synthesis, the finest chemical differences yet tested.
- It uses a matched-pose design on VHL-recruiting SHP2 degraders to isolate the effect of the linker.
- This is a preprint, not yet peer reviewed; the snippet-level abstract available limits detail on the outcome.
💡 PointsLinker tweaks are where PROTAC campaigns burn months of synthesis, so an honest test of whether scoring can separate near-identical analogues is more useful than another headline-grabbing benchmark. Matched poses remove the usual excuse that the method just got the geometry wrong. Even a negative answer helps: it tells us to keep building degradation and cooperativity assays rather than trusting a docked score.
Scoring close linker analogues in PROTAC ternary complexes: A matched-pose study of VHL-recruiting SHP2 degraders ↗
2026-09-30 · ⚗️GPCR–TfR1 targeting chimeras (GTACs) · Nature (Springer Nature)
- GPCR–TfR1 targeting chimeras (GTACs) are bispecific antibodies that pair a receptor binder with a transferrin-receptor binder.
- They drive endocytosis and lysosomal degradation of the GPCR, rather than blocking the orthosteric site.
- Reported for BILF1, RXFP1 and CCR6, covering viral, cancer and immune targets that are hard to drug.
- Signalling, including constitutive activity, was fully shut down, with markedly greater potency than conventional antibody antagonists.
💡 PointsDegrading the receptor sidesteps the usual GPCR headache of finding a clean orthosteric or allosteric small molecule, and it kills constitutive signalling that inverse agonists only partly touch. The catch for my own work: it is an antibody format, so oral exposure and tissue reach are off the table, and TfR1 recruitment brings its own distribution and safety questions. Still, it hands us a genuine alternative mechanism for orphan-like GPCRs where chemistry has stalled.
GPCR antagonism via rewiring of receptor trafficking and degradation ↗
2026-09-30 · ⚗️Soft drug design (topical delivery) · Nature Reviews Drug Discovery (Nature)
- 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.
💡 PointsFor 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.
Soft drugs: design principles and topical applications ↗