Pharmacology · Pharmacology archive
Pharmacology — October 2026
2026-10-23 1 article
A small-molecule BCL9/β-catenin blocker is tested in glioblastoma cells
- Because BCL9, a β-catenin coactivator, had lacked small-molecule inhibitors, its therapeutic value in glioblastoma had not been tested pharmacologically.
- The new inhibitor ZD37-28R was predicted by docking to bind β-catenin, and it disrupted the BCL9/β-catenin interaction in vitro.
- It suppressed β-catenin-driven transcription and reduced proliferation and migration of U87-MG and U251 glioblastoma cells.
Wnt/β-catenin has been a graveyard for small molecules, and a BCL9-selective PPI blocker is a more tractable angle than hitting β-catenin broadly. The open questions are the usual PPI ones: direct biophysical evidence of binding rather than docking, selectivity against other β-catenin partners, and brain exposure for a glioma indication. Treat this as target validation work, not a lead yet.
2026-10-17 2 articles
Molecular glue RPT04402 restores PP2A trimer assembly in high-grade uterine cancer
- The paper describes RPT04402, a molecular glue that restores formation of the PP2A AαB56αC heterotrimer in high-grade uterine cancer.
- Recurrent PPP2R1A scaffold mutations in these tumors impair holoenzyme assembly, which the glue is designed to rescue.
- Company reports describe regressions in preclinical PP2A-mutant models and a license to SpringWorks; this summary rests on the title and secondary sources, not the full text.
Phosphatases are famously hard to drug, so a glue that rebuilds a specific heterotrimer rather than inhibiting an active site is a smart route around that. Here the mutation defines both the patient population and the mechanism, a tidy match. I'd watch how selective it is among the many PP2A B-subunit complexes, since activating the wrong ones is the obvious tolerability worry.
Oral TREM2 agonist VG-3927 reaches the clinic with preclinical and first-in-human data
- The paper reports preclinical and first-in-human evaluation of VG-3927 (SAR448851), an orally dosed small-molecule TREM2 agonist for Alzheimer's disease.
- Public reports describe good tolerability across ascending doses, central nervous system penetration, and a drop in the soluble TREM2 marker in cerebrospinal fluid.
- This summary rests on the article listing and secondary reports, not the full text.
Most TREM2 efforts are antibodies, so a brain-penetrant oral agonist that shifts a CSF pharmacodynamic marker is a notable modality shift. The open question is whether lower soluble TREM2 reflects real receptor activation, since a marker can move without microglial function changing. The first-in-human data show exposure and engagement, not efficacy.
2026-10-13 1 article
Dual MOR/D3R ligand with a lower D3R/MOR ratio shows reduced abuse-related signals in mice
- Dual ligands fuse the MOR partial agonist TRV734 with a D3R-antagonist trans-cyclopropylamine scaffold, aiming at safer opioid analgesics.
- (R)-LS02-14 and TRV734 gave robust antinociception but similar abuse-liability and respiratory-depression signals.
- (R)-LS01-64, with a much lower D3R/MOR ratio, gave modest analgesia but weaker reinforcing and conditioned-reward effects and minimal respiratory impact.
The data argue that the D3R/MOR balance, not mere D3R engagement, sets the behavioral profile, and the best safety came with less analgesia. That is the familiar trade-off, so the open question is whether a ratio exists that keeps efficacy while retaining the reward-dampening effect.
2026-10-05 1 article
DNA origami carrying a barnase variant is built to cleave mutant KRAS mRNA
- Mutant KRAS variants are structurally diverse and lack druggable pockets, which has limited small-molecule inhibitors.
- The authors assemble a degrader on a six-helix-bundle DNA origami scaffold that targets the mRNA rather than the protein.
- One module pairs an engineered barnase variant with a programmable recognition strand, cutting RNA directly without relying on endogenous cellular machinery; a second module is designed for cell penetration.
If KRAS has no pocket worth chasing, going after the mRNA is a fair dodge, and a catalytic barnase gives a clean mechanism: sequence-guided cleavage, no reliance on endogenous machinery. But I would want to see the data before getting excited. How well does the recognition strand discriminate single-base mutants from wild-type KRAS, given barnase's cleavage is catalytic and unforgiving of leakage? And does it survive delivery, with real potency in cells and a sensible comparison to siRNA or ASO?