Daily digest — 2026-09-12

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.

What earns this a second look is the mechanism: an allosteric binder that stays non-covalent until the enzyme's own turnover releases CoA to staple it in place — a genuinely new trick, not just another warhead. Whether it generalizes beyond NatA's odd CoA-release chemistry is unclear, but it's worth filing away as a template for other CoA- or cofactor-dependent enzymes. The selectivity over other NATs despite a conserved active site is the more actionable lesson: skip the catalytic pocket, go allosteric, and you dodge the conservation problem for free. As probe discovery, repurposing tideglusib beats de novo synthesis for speed, but it also means every existing GSK-3β dataset on this molecule is now confounded — nobody should read across to NatA biology from tideglusib phenotypes without new chemical matter. NatA itself looks like a legitimate, underexplored target; this is a probe paper, not a drug paper, but it's the right first step.

Locking down the non-productive Kalirin-Rac1 complex rather than competing head-on for the nucleotide pocket is the smarter play — GTP/GDP affinity is sub-nanomolar, and pan-Rac1 nucleotide-pocket tools like NSC23766 have never been clean. It's the SOS1-KRAS playbook applied to Rho biology, not a new idea, but a good one to borrow. Selectivity across GEF-GTPase pairs is the actual prize, not a burden — Rho-family homology is brutal, so an interface-driven selectivity handle beats trying to differentiate active-site chemistry. What I'd interrogate: fragment merging from XChem hits into covalent leads has a high attrition rate, so two validated compounds (RS-009, MC-278) is a real result, not a given. Before calling these clean probes I want warhead kinetics and full-proteome ABPP, not just the GEF-GTPase panel.