Eight science items today: Hsp90β-selective inhibitors, a DEL-derived MAGL inhibitor, a DNMT1 PROTAC, an HDAC2-selective compound, ENPP1 and colchicine-site leads, an RL fragment-growing tool and QPCT/L screening. Business: ArriVent's phase 3 miss and argenx's Sjögren's setback.
2026-10-08 · ⚗️Tubulin (colchicine-binding site) · Journal of Medicinal Chemistry (ACS)
- Only temozolomide and vorasidenib are approved brain-permeable, orally available drugs for brain cancers, so the team sought new brain-penetrant options.
- SAR work yielded a new class of highly brain-penetrant tubulin ligands; co-crystal structures confirm colchicine-site binding, with the tubulin βT7 and αT5 loops flipped relative to the colchicine-bound state.
- SAR showed high sensitivity to substitution with few indispensable moieties, leading to compound 40 as the clinical candidate.
💡 PointsTubulin binders that actually cross the blood-brain barrier usually die on P-gp efflux or neurotoxicity, so a tight series with strong brain exposure is notable. The flipped βT7/αT5 loops hint at a binding mode worth docking my own colchicine-site scaffolds against. Chronic neurotoxicity is still the question.
Discovery and Optimization of a Novel Brain-Penetrant Colchicine-Binding Site Ligand for Treatment of Glioma ↗
2026-10-08 · ⚗️DNMT1 (PROTAC degrader) · Journal of Medicinal Chemistry (ACS)
- DNMT1 drives fibrogenesis through both catalytic and non-catalytic mechanisms, so the team built PROTAC degraders starting from DC-517 to hit both at once.
- Lead compound B7 mediates ubiquitin-proteasome degradation of DNMT1, lowers global DNA methylation and suppresses profibrotic responses in vitro.
- In vivo, B7 reduced DNMT1 levels and attenuated liver fibrosis, with less collagen deposition and better hepatic function.
💡 PointsDNMT1 is a textbook case for degrading rather than inhibiting, because an active-site inhibitor leaves the scaffolding role untouched. My worry is selectivity for liver and what removing an essential maintenance methyltransferase does in dividing tissue; fibrosis models are forgiving on both counts.
Discovery of Potent, Selective DNMT1 PROTAC Degraders: Simultaneous Blockade of Catalytic and Non-Catalytic Functions for Liver Fibrosis Therapy ↗
2026-10-08 · ⚗️ENPP1 (cGAMP hydrolase, STING pathway) · Journal of Medicinal Chemistry (ACS)
- ENPP1 hydrolyzes cGAMP in the tumor microenvironment and so dampens STING-driven antitumor immunity.
- Inspired by the phosphate-based inhibitor STF-1084, the team made non-nucleotide inhibitors with a boronic acid zinc-binding group, leading to compound 36, which stays potent across pH.
- Compound 36 boosted cGAMP-mediated STING activation in vitro and gave tumor growth inhibition as monotherapy in a syngeneic CT26 model, with a synergistic effect alongside oxaliplatin and no observed toxicity.
💡 PointsPhosphate- and phosphonate-type ENPP1 binders have always struggled with permeability and exposure, so swapping in a boronic acid zinc binder is a cleaner route. Designing for acidic-pH activity is the smart part, since that is where the enzyme works. Single-agent efficacy by IP dosing is modest, so oral exposure and boronic acid stability are my next questions.
Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy ↗
2026-10-08 · ⚗️HDAC2 (isoform-selective inhibitor) · Journal of Medicinal Chemistry (ACS)
- KTT-1 (compound 12) was identified as HDAC2-selective by evaluating both thermodynamics and kinetics of enzyme–inhibitor binding, rather than affinity alone.
- Crystallography of HDAC2 with the compound, plus quantum chemical calculations on model compounds, suggests its 2-furanyl group drives the selectivity.
- In cells it preferentially inhibited HDAC2 over the highly homologous HDAC1 and promoted neurite outgrowth; in stress-vulnerable mice it improved memory and depression-like behavior.
💡 PointsScreening on residence time rather than IC50 alone is how you get past the near-identical HDAC1/2 active sites, and a furanyl contact backed by both crystallography and QM is a clean, testable rationale. Cellular HDAC2-over-HDAC1 preference is rare, so I'd want it confirmed in neurons with real brain exposure.
Discovery of an HDAC2-Selective Inhibitor via Enzyme−Inhibitor-Binding Thermodynamics/Kinetics as a Prospective Neurological Disorder Drug ↗
2026-10-08 · ⚗️Hsp90β (isoform-selective inhibitors) · Journal of Medicinal Chemistry (ACS)
- Pan-Hsp90 inhibitors stalled clinically because of their broad inhibition, so Hsp90β-selective indazolone compounds have been pursued, though earlier ones needed long optimization to become drug-like.
- This work modifies the northern indazolone fragment and the southwestern appendage at the same time, testing whether the best traits of each region can be combined.
- The resulting chimeric inhibitors retain Hsp90β affinity and selectivity while shifting key pharmacokinetic parameters.
💡 PointsMerging two independently optimized vectors is a sensible, low-risk move, and selectivity surviving the merge suggests the β-specific pocket tolerates more change than I feared. What would decide it for me is tissue exposure and tolerability, since that is where pan-inhibitors failed.
Chimeric Hsp90β-Selective Inhibitors Confer Enhanced Affinity, Selectivity, and Drug-Like Properties ↗
2026-10-08 · ⚗️MAGL (monoacylglycerol lipase); DNA-encoded library hit · Journal of Medicinal Chemistry (ACS)
- A bicyclopiperazine hit from a DNA-encoded library was optimized by structure-guided design into compound 1.5 (MAGLi 432), a reversible MAGL inhibitor.
- The compound combines high potency, selectivity over other serine hydrolases and CNS drug-like properties, with a favorable oral half-life in rats.
- It inhibited MAGL in human brain homogenate and worked in mouse neuroinflammation models; the campaign was steered by a translational "Five-Star Matrix" framework.
💡 PointsReversibility is the part I'd want here, since irreversible MAGL agents ran into CB1 desensitization on chronic dosing. A non-covalent DEL chemotype that already shows target engagement in human brain tissue is a good template, and I'd steal the habit of testing in human tissue early rather than at the end.
Translational Application of the Five-Star Matrix for the Structure-Guided Optimization of a Bicyclopiperazine DEL Hit into Bcpz 1.5: A Potent Monoacylglycerol Lipase Inhibitor with Functional Inhibition in Human Brain Homogenate and Efficacy in Neuroinflammatory Models ↗
2026-10-08 · ⚗️QPCT/QPCTL (glutaminyl cyclases) · ACS Medicinal Chemistry Letters (ACS)
- QPCT and Golgi-bound QPCTL convert N-terminal glutamines to pyroglutamate, affecting Aβ oligomerization, chemokine stability and CD47–SIRPα signaling.
- A virtual screen selecting under 0.1% of an in-house library, based on similarity to bioactive conformations of known inhibitors, delivered new chemotypes and sped up hit discovery.
- Structure-guided optimization of a quinazolidinone series gave the cellular tool compound BI-3614, with improved activity over earlier inhibitors.
💡 PointsScreening under a tenth of a percent and still finding fresh chemotypes is the efficiency argument for conformation-based similarity searching. The old QPCT inhibitors leaned on metal-binding groups, so a new cell-active series is welcome for CD47 pyroglutamate biology. QPCT versus QPCTL selectivity is what I'd check first.
Accelerated Hit Identification and Optimization of a Novel Class of Cellularly Active QPCT/L Inhibitors ↗