Eight science items today: an HDAC6 L2-pocket series, a STING inhibitor for pancreatitis, a TFEB inhibitor grown from eltrombopag, an MprB antivirulence series for tuberculosis, a tubulin/HDAC8 dual inhibitor, a PDIA3 antiviral, a peptide-like DEL and a PI4KIIIβ/HDAC dual HCV series. One business item: safety questions around Neurocrine's Vykat XR.
2026-10-12 · ⚗️MprB (Mtb sensor histidine kinase) · Journal of Medicinal Chemistry (ACS)
- The earlier hit BTP15 protects host cells from Mtb-induced death by blocking phagosomal escape through MprB inhibition, but had poor pharmacokinetics.
- New benzothiophene analogues were screened for MprB inhibition, microsomal stability, toxicity and ex vivo efficacy in THP-1 and MRC-5 cells.
- The aim is a virulence-blocking route that avoids killing the bacterium directly, which may reduce resistance pressure.
💡 PointsAntivirulence is attractive on paper, but the hard part is demonstrating efficacy without a bactericidal readout. I'd look hardest at whether the stability gains translate into in vivo exposure, since BTP15's problem was PK, and at whether MprB engagement is shown cleanly in the infected-cell setting.
Antivirulence Benzothiophenes Inhibit Intracellular Mycobacterium tuberculosis by Targeting the Sensor Histidine Kinase MprB ↗
2026-10-12 · ⚗️TFEB (transcription factor) · Journal of Medicinal Chemistry (ACS)
- TFEB, a transcription factor long seen as undruggable, was approached starting from eltrombopag, which has weak TFEB inhibitory activity alongside its Tpo-R agonism.
- SAR optimisation gave DCL1191, which binds TFEB, disrupts TFEB–DNA binding and shows reduced Tpo-R and MITF activity; modelling and mutagenesis support the binding mode.
- It represses TFEB target genes, blocks autophagic flux and is orally bioavailable, with activity in autophagy-hyperactivated glioblastoma cells.
💡 PointsStarting from a marketed drug with a known off-target is a smart way into a transcription factor, because you inherit drug-like properties. The real test is the MITF/TFE3 family: if selectivity over close paralogues holds, this is a genuine tool compound rather than another autophagy-flavoured cytotoxin.
Development of DCL1191 as a Potent, Selective and Orally Bioavailable Inhibitor for Autophagy-Associated Transcription Factor EB (TFEB) ↗
2026-10-12 · ⚗️HDAC6 · Journal of Medicinal Chemistry (ACS)
- Second-generation HDAC6 inhibitors were designed from X-ray structures of earlier compounds bound to the zebrafish HDAC6 catalytic domain.
- Co-crystal structures of two leads showed engagement of S531 in the L2 loop; cells showed raised acetylated tubulin without a clear histone acetylation change.
- One lead cut A549 viability in 2D and 3D culture through pro-autophagic signalling and also affected phase-separation behaviour.
💡 PointsGrabbing the L2 loop is the obvious handle for isoform selectivity: the CD2 pocket is conserved, the loop is not. Acetylated tubulin up and histones flat is the readout I want before believing a selectivity claim. I'd still ask for a broad HDAC panel and some PK before getting excited about the autophagy story.
Structure-Based Design of HDAC6 Inhibitors Targeting the L2 Pocket: Modulating Autophagy and Liquid−Liquid Phase Separation in Lung Cancer ↗
2026-10-12 · ⚗️PDIA3 (host ER oxidoreductase) · Journal of Medicinal Chemistry (ACS)
- PDIA3, an ER oxidoreductase involved in folding glycosylated viral envelope proteins, is an underexplored host target for antivirals.
- A new N-hydroxyindole-2-carboxamide class, exemplified by AV22, inhibits PDIA3 and shows broad activity against major human respiratory viruses.
- In coronavirus-infected cells AV22 raised release of non-infectious particles and reduced disulfide bond formation in spike.
💡 PointsHost-directed antivirals dodge resistance but live or die on the therapeutic window, because PDIA3 does real work in uninfected cells. An N-hydroxy group is also a flag for me: metal binding and metabolic liability can both bite. I'd look first at cytotoxicity margins and microsomal stability.
Development of N-Hydroxyindole-2-Carboxamides as New Host-Targeted Broad-Spectrum Antiviral Agents Against Human Respiratory Viruses ↗
2026-10-12 · ⚗️DNA-encoded library (peptide-like) · ACS Medicinal Chemistry Letters (ACS)
- A three-cycle, peptide-like DEL of 403,200 compounds was built, with a chemical space model of 4,774 commercial amino acids used to find under-represented building blocks.
- Affinity selections were run against three targets to compare library performance.
- Selection against carbonic anhydrase II recovered the known sulfonamide pharmacophore, supporting the computational design approach.
💡 PointsRecovering the sulfonamide on CA II is the expected sanity check, not proof of lead-like coverage. Peptide-like DELs often return big, polar hits, so what I'd judge is how many selected compounds sit in usable property space off-DNA, and how the two other targets behaved.
Design, Synthesis, and Comparative Selection Analysis of a Chemically Diverse Peptide-Like DNA-Encoded Library ↗
2026-10-12 · ⚗️PI4KIIIβ / HDAC · Journal of Medicinal Chemistry (ACS)
- Host-directed dual inhibition of PI4KIIIβ and HDACs had not previously been reported for hepatitis C, where resistance to direct-acting antivirals remains a concern.
- A series of thiazolamide-based dual inhibitors was designed, synthesised and evaluated.
- Lead compounds showed potent enzymatic inhibition of both targets together with anti-HCV activity.
💡 PointsWith DAAs curing most patients, the case for a host-directed HCV drug is hard to make commercially, and a dual PI4KIIIβ/HDAC profile adds tox risk. I read this as a good exercise in multitarget design, but would want to see cytotoxicity and kinase selectivity before calling the window real.
Discovery of Thiazolamide-based PI4KIIIβ/HDAC Dual Inhibitors with Potent Activity against Hepatitis C Virus ↗
2026-10-12 · ⚗️STING · Journal of Medicinal Chemistry (ACS)
- SAR work identified D4, which binds STING directly and blocks its oligomerization and downstream TBK1/IRF3 signalling.
- In macrophages it restored phagocytosis, autophagic flux and mitochondrial function while dampening NLRP3-linked pyroptosis.
- D4 was orally exposed and well tolerated at high dose, and cut pancreatic injury and enzyme levels in a caerulein/LPS model; STING knockdown looked similar.
💡 PointsMost STING programs chase agonists for oncology; an orally available inhibitor for an acute inflammatory indication is a different bet. The knockdown phenocopy is reassuring on mechanism, but I'd want to know how it behaves across species, since STING ligand pockets are notoriously species-dependent, and whether an acute dosing window is realistic in patients.
Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis ↗
2026-10-12 · ⚗️Tubulin / HDAC8 · Journal of Medicinal Chemistry (ACS)
- The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
- Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
- It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.
💡 PointsHDAC8 is a less crowded choice than the usual HDAC6/class I pairing, and pairing it with a tubulin binder is mechanistically coherent. My worry is the classic one for dual hybrids: the two activities rarely scale together, so I'd want evidence that HDAC8 inhibition, not just the tubulin arm, contributes to the in vivo effect.
Discovery of a Novel Dual Inhibitor Targeting Tubulin and Histone Deacetylase 8 for Treatment of the Ovarian Cancer ↗