Daily digest — 2026-10-16

Phenotypic screening with a covalent library is a sensible way to find chemotypes that target-based approaches would never pick. The weak point is deconvolution: until the cysteine targets are identified, a microtubule depolymerizer risks being one more tubulin binder. Worth tracking for the non-tubulin hits.

This is the unglamorous but valuable kind of paper: a compound used as an HDAC11 tool turns out to hit HDAC6 hardest. Any phenotype published with Elevenostat now has an attribution problem. Before I reuse an inhibitor as a probe, I want full-panel selectivity and a matched inactive control, which this case argues for.

State dependence is a leading suspect for why NaV1.7 programs keep failing clinically, so a probe that blocks resting and inactivated states alike is a good way to test that hypothesis. NaV1.1 activity is a flag for seizure-related liability, and I'd want a binding-site assignment before reading too much into the profile.

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.

BI-3802 is a polymerizing degrader with a peculiar mechanism, so a conventional CRBN-recruiting PROTAC from a fresh tricyclic core is a useful alternative route to BCL6 removal. Oral efficacy matters most here; I'd want to see how the molecule balances size and permeability, and whether degradation depth tracks with tumor response across non-OCI-LY1 lines.

MTA-cooperative PRMT5 inhibitors are crowded, and brain exposure is the clear differentiator: MTAP deletion is common in glioblastoma, where most competitors can't reach the tumor. A clinical readout appearing in a medicinal chemistry paper is rare. I'd now look at hematologic safety, the usual liability for this class, and at how much of the intracranial effect is truly unbound-drug driven.

Membrane transporters rarely give such a clean example of structure-driven design: two cryo-EM pockets, one merged series, in vivo pharmacodynamics from a simple urinary readout. The mouse potency shift is the practical snag for efficacy models, so the primate retention is reassuring. Next I'd want to know the margin for amino acid depletion.

Protein–protein interactions with a receptor ectodomain are tough targets, so three orthogonal assays is the right way to weed out artifacts. I'd treat the hits cautiously until they show activity in cellular tau-uptake assays and clear LRP1's many other ligands, such as ApoE and RAP, without broad liabilities.