Daily digest — 2026-11-03

A cysteine-directed route that sidesteps the pSer/Thr pocket is appealing if phosphate-mimetic ligands raise permeability concerns, though that depends on the paper's own data. Not in the summary: kinact/KI rather than a bare potency claim, intact-protein MS for stoichiometry, a Cys113Ala control and proteome-wide selectivity. Whether fragment-derived warheads are selective or merely reactive is the question to answer.

Chalcones carry a Michael-acceptor enone, so a glutathione-trapping assay and a jump-dilution washout would test the reversibility claim for MBC21. The Tyr326 stacking story currently rests on modeling. A matched alkoxy-chain series benchmarked against reference MAO-B inhibitors such as safinamide would show whether this chemotype adds anything new.

Linker-length and exit-vector SAR would show whether this is a general toolkit or a narrow geometry window; dimerizer activity can be geometry-sensitive, and a hook effect at high dose is a likely failure mode. Two checks matter most: a monomeric-ligand competition control, and a potency and kinetics comparison with FKBP-based dimerizers, including any liabilities of BromoTag's ligand.

Preferential HDAC3 loss may partly reflect the entinostat warhead's own isoform profile, so the first things to look for are a non-binding or inactive-epimer control and a way to separate degradation from inhibition, such as HDAC3 knockout or proteasome and neddylation blockade. A comparison with other HDAC3-selective PROTACs would also show whether the VHL versus CRBN choice shapes isoform bias.

Tumor overexpression is a hypothesis, not yet a therapeutic window: matched normal-tissue expression and a ligase-knockout control would be needed before selectivity counts as shown. For a PROTAC program, the practical test is a head-to-head against CRBN and VHL on ternary-complex cooperativity and degradation rate with one target warhead, plus a look at what chemistry current recruiters use and how clean they are proteome-wide.

A preference for HDAC6 over HDAC1 is notable, but docking alone shouldn't settle it. A full isoform panel and a cellular readout comparing tubulin and histone acetylation would test it. Whether the anti-inflammatory effect is on-target is a separate question, answerable with an HDAC6 knockout or tool-inhibitor control; binding kinetics of the zinc-binding group may also shape isoform selectivity.

The hybrid logic is neat, but BI-2536 is known as a PLK1 inhibitor, so a PLK1 counter-screen would show how much of the cell potency comes from VEGFR-2 and BRD4. In vivo, a matched-exposure combination arm and tumor MYC knockdown as a BRD4 engagement readout would test whether "beats the combination" holds up.

The dual-action label needs a control it doesn't yet have: a FLAP-inactive analog or a 5-LO-null cell line, to show the antiproliferative effect isn't plain scaffold cytotoxicity. The polar aliphatic address groups are the interesting part. It's worth checking whether they lower lipophilicity compared with earlier FLAP chemotypes, so solubility and clearance are the sensible next measurements.

Whether glue-induced kinase degrons are structural motifs one can design toward, or quirks of individual scaffolds, is still open. Matched kinase inhibitors and ternary-complex data would help separate true degradation from inhibitor-driven effects. A useful next step is mapping which ligand edits move the exit vector toward the G-loop, then testing how far that logic generalizes across kinases.