Target biology, in vivo efficacy, translational research, DMPK and safety.https://pharmadigest.net/enhttps://pharmadigest.net/en/articles/2026-10-23-bcl9-beta-catenin-inhibitor-glioma/https://pharmadigest.net/en/articles/2026-10-23-bcl9-beta-catenin-inhibitor-glioma/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.Fri, 23 Oct 2026 00:00:00 GMTPharmacologyBCL9β-cateninWntglioblastomaprotein-protein interactionhttps://pharmadigest.net/en/articles/2026-10-17-rpt04402-pp2a-molecular-glue-uterine-cancer/https://pharmadigest.net/en/articles/2026-10-17-rpt04402-pp2a-molecular-glue-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.Sat, 17 Oct 2026 00:00:00 GMTPharmacologyPP2Amolecular glueuterine cancerphosphatasehttps://pharmadigest.net/en/articles/2026-10-17-vg-3927-oral-trem2-agonist-alzheimers/https://pharmadigest.net/en/articles/2026-10-17-vg-3927-oral-trem2-agonist-alzheimers/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.Sat, 17 Oct 2026 00:00:00 GMTPharmacologyTREM2Alzheimer's diseaseoral small moleculefirst-in-humanhttps://pharmadigest.net/en/articles/2026-10-13-mor-d3r-dual-target-ligands-ls01-64-opioid/https://pharmadigest.net/en/articles/2026-10-13-mor-d3r-dual-target-ligands-ls01-64-opioid/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.Tue, 13 Oct 2026 00:00:00 GMTPharmacologyopioidMORdopamine D3dual-target ligandshttps://pharmadigest.net/en/articles/2026-10-05-dna-origami-barnase-rna-degrader-mutant-kras-mrna/https://pharmadigest.net/en/articles/2026-10-05-dna-origami-barnase-rna-degrader-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.Mon, 05 Oct 2026 00:00:00 GMTPharmacologyKRASDNA origamiRNA degraderbarnasemRNA targetinghttps://pharmadigest.net/en/articles/2026-09-16-gpr41-endotoxemia-autophagy-target/https://pharmadigest.net/en/articles/2026-09-16-gpr41-endotoxemia-autophagy-target/GPR41/FFAR3, a short-chain-fatty-acid-sensing GPCR, was tested as a target for dampening gut-derived endotoxemia in a macrophage model of endotoxin stress. The selective agonist AR420626 activated GPR41 and blunted downstream pro-inflammatory signaling, cutting output of nitric oxide, IL-6, MCP-1, and iNOS. This anti-inflammatory effect tracked to suppression of NF-κB signaling, the central pathway driving those mediators. Agonist treatment also boosted autophagic flux, marked by increased LC3-I-to-LC3-II conversion. Blocking autophagy pharmacologically erased AR420626's protective effect, indicating autophagy induction is mechanistically required rather than incidental to the anti-inflammatory action. Findings position GPR41 as a druggable node linking gut microbial metabolite sensing to control of systemic inflammation in metabolic endotoxemia.Wed, 16 Sep 2026 00:00:00 GMTPharmacologyGPCRnew drug targetmetabolic diseaseinflammationNF-κB