I-0436650 / IRBM - LARVOL DELTA

Discovery and Preclinical Characterization of I-0436650, a Selective SHP2 Allosteric Inhibitor for RAS-Driven Cancers. (PubMed, J Med Chem) - "I-0436650 is a low nanomolar allosteric inhibitor of human wild-type (wt) SHP2 and strongly inhibits ERK phosphorylation in cells. It exhibits antiproliferative activity in EGFR- and RAS-dependent cell lines, suppresses tumor growth as a single agent in xenograft models, and delays tumor relapse when combined with inhibitors of the same pathway, demonstrating the potential of vertical inhibition strategies."

Journal • Preclinical • Oncology • EGFR

Discovery of I-0436650, a potent and selective SHP2 allosteric inhibitor for the treatment of RAS driven solid tumors (EACR 2023) - "In particular, the combination of I-0436650 with the KRAS G12C inhibitors Sotorasib and Adagrasib, the EGFR inhibitor Osimertinib and the CDK4/6 inhibitor Ribociclib results in synergistic growth inhibition of multiple RTK/KRAS-driven cancer cell lines. Further, I-0436650 effectively inhibits tumor growth in vivo in SHP2-dependent human xenograft models.ConclusionI-0436650 is a potent, selective and orally available SHP2 inhibitor with opportunity for once-a-day dosing in humans. Of note, its synergistic effect when combined with selected pharmacological agents makes it a valuable therapeutic option against a multitude of RTK/KRAS-driven tumors and metastases."

Oncology • Solid Tumor • KRAS

Discovery of I-0436650, a potent and selective SHP2 allosteric inhibitor for the treatment of RAS driven solid tumors (AACR-NCI-EORTC 2022) - "I-0436650 is a potent, selective an orally available SHP2 inhibitor with potential for once-a-day dosing in humans. Of note, its predicted brain permeability in humans makes it a potential therapeutic agent against SHP2i responsive brain tumors and metastases. No"

Brain Cancer • Oncology • Solid Tumor • EGFR