Six science items today, all small-molecule and degrader work: a non-competitive KDM6B inhibitor, a G protein-biased GPR183 agonist, STK33 male-contraceptive indazoles, a TLR4 PROTAC, VHL-based HDAC6 degraders and dual MOR/D3R opioid ligands. No new business items cleared the bar.
2026-10-12 · ⚗️HDAC6 (VHL-recruiting PROTACs) · chemRxiv
- A solid-phase route enabled systematic variation of VHL ligand, exit vector and linker in vorinostat-derived HDAC6 PROTACs.
- Longer, semi-rigid linkers gave the best degradation; the lead compounds degraded HDAC6 preferentially in MM.1S and MV4-11 cells.
- A matched non-degrading control with similar HDAC inhibition was clearly less antiproliferative, pointing to degradation itself as the driver.
💡 PointsThe non-degrading control with matched enzyme inhibition is the kind of experiment that separates degradation from plain inhibition, and it favors the PROTAC. Preferential, not exclusive, HDAC6 selectivity from a vorinostat-like warhead is the weak point; a more isoform-selective ligand might sharpen it.
Solid-phase synthesis and structure-degradation relationships of VHL-recruiting PROTACs for preferential histone deacetylase 6 degradation ↗
2026-10-10 · ⚗️TLR4 (PROTAC degrader) · ACS Medicinal Chemistry Letters (ACS)
- Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
- The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
- Protection was also seen in zebrafish, extending PROTAC use beyond oncology.
💡 PointsUsing a PROTAC to rescue a weak natural-product binder is clever, but TLR4 is a membrane receptor and the evidence here is thin on which E3 ligase is engaged and on ternary-complex dependence. I'd ask for rescue experiments with ligase and proteasome inhibitors before believing the mechanism.
Enhancing Natural Product Therapy with PROTACs: Targeted Degradation of TLR4 Confers Potent Endothelial Protection ↗
2026-10-09 · ⚗️GPR183 (EBI2) biased agonists · Journal of Medicinal Chemistry (ACS)
- SAR optimization of earlier virtual-screening hits, themselves derived from the antagonist NIBR189, gave full GPR183 agonists with complete G protein bias.
- The lead, TUG-2604, matches the endogenous oxysterol 7α,25-OHC in potency and efficacy without recruiting β-arrestin2.
- It failed to drive human dendritic cell migration on its own and blocked migration induced by the oxysterol.
💡 PointsTurning an antagonist-derived hit into a full agonist with complete G protein bias is not routine, and the migration data hint that β-arrestin signaling carries the chemotaxis. For anyone weighing GPR183 in inflammation, this is a clean tool to separate the two arms before committing to a direction.
Development of Potent G Protein Pathway-Biased GPR183 Agonists ↗
2026-10-09 · ⚗️KDM6B / JmjC histone demethylases · Journal of Medicinal Chemistry (ACS)
- Scaffold-hopping virtual screening produced a diaryl pyrimidine-guanidine series against the JmjC demethylase KDM6B, which is overexpressed in cervical cancer.
- The optimized lead matched GSK-J4 in enzyme potency but is non-competitive with 2-oxoglutarate, a different binding logic from most JmjC inhibitors.
- Despite pan-KDM activity in vitro, it selectively raised H3K27me3 in C33A cells and slowed xenograft growth.
💡 PointsMost JmjC inhibitors live or die on 2-OG-site chemistry and its polarity baggage, so a non-competitive series is a genuinely different starting point. I'd want to know why enzyme-level pan-KDM activity collapses to H3K27me3 selectivity in cells, and what the guanidine does to permeability.
Discovery of Diaryl Pyrimidine-Guanidine Derivatives as Jumonji C Domain-Containing Lysine Histone Demethylase (KDM) Inhibitors with In Vivo Anti-Cervical Cancer Activity ↗
2026-10-09 · ⚗️STK33 (nonhormonal male contraceptive target) · Journal of Medicinal Chemistry (ACS)
- SAR and property work on the 3-(biphenylethynyl)-1H-indazole scaffold behind CDD-2807 targeted its poor kinetic solubility.
- CDD-3094 kept nanomolar cellular potency while gaining solubility, lowering hERG liability and showing a clean broad kinase panel.
- A co-crystal structure guided changes against the main off-target CLK4, giving a strongly selective biochemical tool whose cellular potency dropped.
💡 PointsThis is a textbook potency-versus-properties trade: solubility fixed in CDD-3094, then selectivity bought at the price of cell activity. For a contraceptive, where the safety bar is far higher than in oncology, the CLK4 discrimination matters more than raw potency; the next step is recovering permeability.
Design, Synthesis, and Pharmacological Profiling of Serine/Threonine Kinase 33 (STK33) Inhibitors for Nonhormonal Male Contraception ↗