Discovery of Zoldonrasib (RMC-9805), a Potent and Orally Bioavailable RAS(ON) G12D-Selective, Covalent, Tri-Complex Inhibitor for the Treatment of Patients with RAS G12D-Addicted Cancers

Abstract RAS mutations are among the most frequent oncogenic drivers in human cancer, and KRAS G12D is one of the most prevalent RAS alterations occurring in pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer. Here, we describe the structure-based SAR journey that led to the discovery of zoldonrasib (RMC-9805), an orally bioavailable RAS(ON) G12D-selective, covalent, tri-complex inhibitor. Discovery of an aziridine-2-carboxamide-based warhead and a rigid spirocyclic linker enabled selective covalent engagement of KRAS G12D in its active, GTP-bound state. Zoldonrasib exhibited potent inhibition of KRAS G12D signaling and proliferation in KRAS G12D-dependent cancer cells, favorable ADME and cross-species pharmacokinetic properties, and selectivity over RAS-independent cellular models. In vivo, zoldonrasib produced deep and durable suppression of tumor RAS pathway signaling and induced dose-dependent tumor regressions in KRAS G12D-driven xenograft models. Currently, zoldonrasib is in clinical evaluation for KRAS G12D mutant solid tumors.