Daily digest — 2026-10-30

Starting from BI-167107 and Cimaterol is the smart move: both are well-validated agonist chemotypes with known binding poses, so inserting the azo unit is a bioisosteric swap rather than blind scaffold hopping. The open question is how the trans form stays truly silent when the parent ligands are so potent. Tunable relaxation and efficacy also make this a usable SAR set for GPCR activation kinetics, not just a tool compound.

Is a proline linker really what cleans up the gut, or is it just the overall hydrophilicity of the Tc complex? Without matched controls I'd bet on the latter, which is still useful because it makes hydrophilicity a tunable handle. 2-Nitroimidazole is the old, validated hypoxia warhead, so the novelty lies in linker and coligand choice, and six complexes give a meaningful structure-activity comparison.

Chloroacetamides are blunt warheads, so my first question is proteome-wide selectivity, and the in situ chemoproteomics answering with HMG-CoA synthase is reassuring. Targeting the mevalonate pathway in Gram-positives is a refreshing departure from beta-lactam and ribosome chemotypes. The caveat: a crystal structure of a covalent adduct says little about whether non-covalent recognition can be tuned toward a tamer warhead.

Verubulin is a colchicine-site binder with a basic quinazoline core, so the quaternary-ammonium trick makes sense: the tertiary amine is the natural handle, and quaternizing it avoids amide and carbamate linkers that kill potency. The catch is release. If the payload comes off as a charged species, low bystander effect is predictable, and that limits use in heterogeneous tumours. Still, a non-auristatin, non-maytansinoid tubulin payload adds welcome diversity.

Most of our macrocycle linkers are flat aryl or amide-heavy, which is exactly what hurts permeability and solubility. An sp3-rich cyclophane tether occupies a genuinely different shape space, and building it from SPPS-compatible amino acids means a library is actually feasible. The open question: does the linker rigidity preorganize the binding conformation, or just add lipophilicity?

Clean silence on FXR and LXRα is what I'd care about most, since sterol scaffolds usually light up every oxysterol-sensing receptor. The alcohol-to-acid switch turning RORγ preference into pan-ROR activity hints at a polar head-group contact in the pocket, making the tail the tuning knob. Semi-synthesis keeps the cyclopropyl side chain accessible, but a non-steroidal comparison should precede any claim of novelty.

PLK1 selectivity is the right thing to chase here, since Wee1 and PLK1 both land in mitotic control and cell-cycle readouts will blur if an inhibitor hits both. With no binding mode in the abstract, it is unclear whether selectivity comes from the carboxamide or the aminopyrimidine hinge binder. Oral exposure despite only moderate microsomal stability suggests a tractable core; the SAR table will show how far it can be pushed against adavosertib-type chemotypes.

Designing for low permeability plus high systemic clearance runs against what we usually chase in an sGC stimulator, and it is a clean way to buy lung selectivity without a gated delivery trick. The worry is how much lung retention depends on formulation and particle deposition rather than the molecule. Long target residence time is what should make once-daily dosing plausible.