Abstract 2677: JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models

Abstract

Abstract Activation of the mitogen-activated protein kinase (MAPK) pathway by oncogenic mutations in RAS and RAF is a frequent driver of human cancer. Targeting specific components of the pathway is a precise and rational route to deliver benefits to cancer patients with high unmet therapeutic needs. The RAF kinase proteins (ARAF, BRAF, CRAF) are core pathway components which mediate MAPK signaling. Mutations in these critical signaling proteins leads to constitutive activation of the MAPK pathway and tumor growth. Using state of the art screening methodologies and medicinal chemistry we discovered and developed a next generation pan-RAF kinase inhibitor, JZP815, which potently inhibits wild-type and mutant RAF kinases in cell-free and cell-based assays. JZP815 is a selective RAF kinase inhibitor that suppresses all 3 RAF kinase family members at low-to-sub nanomolar potencies in cell-free assays. Moreover, in tumor cells JZP815 does not induce significant paradoxical pathway activation, observed with approved 1st generation BRAF-selective inhibitors, while demonstrating equivalent potencies for MAPK pathway inhibition driven by either mutant RAF monomers or RAS-induced RAF dimers in tumor cells. JZP815 significantly inhibited tumor growth as a single agent in multiple mouse xenograft solid tumor models harboring RAS and/or BRAF mutations. Furthermore, JZP815’s favorable pharmacokinetic profile sustained on-target pathway pharmacodynamic responses in a predictable dose and time dependent manner. JZP815 demonstrated enhanced activity when combined with inhibitors of other MAPK pathway components in both class 2 and class 3 mutant BRAF patient-derived tumor cells ex vivo, and KRAS mutant NSCLC and CRC xenografts in vivo. In summary, JZP815 is a potent and selective pan-RAF inhibitor that is orally bioavailable in multiple preclinical species with a well-behaved safety profile and pharmacokinetic properties predicted to provide drug exposure required for target engagement in humans, and therefore suitable for advancing into first-in-human trials. Citation Format: Robert Hauptschein, Simon Woodcock, Andrew Belfield, Helen Mason, Dorottya Keppel, Svetlana Markova, Kyuri Kim, Shane Roller, Caroline Phillips, Clifford D. Jones, Robin C. Humphreys. JZP815, a potent and selective pan-RAF inhibitor, demonstrates efficacy in RAF and RAS mutant tumor pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2677.