Discovery andCharacterization of RP04340 : A Highly Potent and OrallyActive Pan-KRAS PROTAC Degrader

Abstract Targeting diverse KRAS mutations with a single agent remains a significant challenge in oncology. Here, we report the discovery and characterization of RP04340, a potent and orally bioavailable pan-KRAS PROTAC degrader. Starting with a structure-based pan-KRAS inhibitor capable of forming a critical hydrogen bond with Tyr96, systematic optimization led to a PROTAC with broad-spectrum KRAS degradation, oral bioavailability, and drug safety profiles. RP04340 potently degrades multiple KRAS mutants, without affecting HRAS, NRAS, or known CRBN neosubstrates, and exhibits robust antiproliferative activity in various cancer cell lines. Orally administered in mice, RP04340 shows sustained exposure, leading to KRAS degradation and downstream signaling suppression. In mouse xenograft models (KRAS G12C, G12D, and G12V), once-daily oral administration of RP04340 resulted in tumor regression and longer-lasting tumor suppression compared to the clinical-stage pan-RAS inhibitor RMC-6236. With its promising efficacy and druglike properties, RP04340 represents a compelling candidate for KRAS-driven cancers.