Discovery and Characterization of RP03707: A Highly Potent and Selective KRASG12D PROTAC

KRAS^G12D, the most prevalent oncogenic mutation in KRAS-associated tumors, represents a highly sought-after drug target for cancer treatment. In this study, we explored a KRAS^G12D protein degradation approach using the PROTAC technology for the treatment of KRAS^G12D mutant tumors. Through the rational design of the KRAS^G12D binder and proper selection of the linker and the E3 ligase ligand, we constructed PROTACs and identified RP03707 as a CRBN-involving, highly potent, and selective KRAS^G12D degrader. RP03707 effectively inhibits tumor cell growth in multiple KRAS^G12D cell lines. It also exhibits prolonged PK/PD effects and excellent efficacy in mouse CDX models bearing KRAS^G12D tumors, highlighting its potential for the treatment of KRAS^G12D-driven tumors in clinical settings.