STING agonist / Nimbus Therap - LARVOL DELTA

NTX-452: a non-covalent, potent, selective and highly efficacious WRN inhibitor with best-in-class potential for the treatment of MSI-H tumors (AACR 2025) - "Washout studies using covalent inhibitors revealed that substantial target engagement was lost in MSI-H cells within 24- hours, suggesting rapid WRN resynthesis may limit sustained target inhibition...The preclinical profile of non-covalent NTX-452 was characterized and compared to clinical-stage WRN inhibitors, including those from Novartis (HRO761, non-covalent) and Roche/Vividion (RO7589831, covalent)...Moreover, NTX-452 promoted durable tumor regression and complete responses in MSI-H PDX models that were refractory to immunotherapy (anti-PD1) or chemotherapy. Lastly, resistance to clinical stage WRN inhibitors was explored and the potential for NTX-452 efficacy in WRN inhibitor resistant cell lines and tumors was evaluated.Taken together, our results highlight the broad, best-in-class potential of NTX-452 in MSI-H tumors and support its advancement to clinical evaluation."

MSI-H • Endometrial Cancer • Microsatellite Instability • Oncology • Solid Tumor • MSI • WRN

SIK2 selective inhibitors demonstrate dual anti-inflammatory and mucosal repair profiles in human ex vivo models of Ulcerative Colitis (ECCO-IBD 2026) - "Among the three SIK isoforms, SIK2 exhibits the highest activity in myeloid cells and uniquely enhances the production of anti-inflammatory cytokine IL-10 when selectively inactivated, distinguishing it from SIK1 or SIK3 LOF...To assess SIK2 inhibition in diseased tissue, colon explants from Ulcerative Colitis patients were collected and cultured ex vivo with the JAK1 inhibitor upadacitinib or SIK2 selective inhibitors for 18 hours...Conclusion Our first-in-class, selective SIK2 inhibitors suppress key proinflammatory cytokines while promoting expression of genes related to tissue repair in human ex vivo models of Ulcerative Colitis. These findings support SIK2 as a novel oral therapeutic approach for Inflammatory Bowel Disease, conferring both anti-inflammatory and tissue reparative benefits for patients."

IO biomarker • Preclinical • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis • CCL3 • CXCL10 • IL10 • IL12A • IL1B • IL1R1 • IL23A • IL6 • MUC2 • OCLN • SIK1 • TLR4 • TNFA

Inter-organelle cross-talk supports acetyl-coenzyme A homeostasis and lipogenesis under metabolic stress. (PubMed, Sci Adv) - "Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations."

Journal • ACSS2