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

KRASG12D, 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 KRASG12D protein degradation approach using the PROTAC technology for the treatment of KRASG12D mutant tumors. Through the rational design of the KRASG12D 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 KRASG12D degrader. RP03707 effectively inhibits tumor cell growth in multiple KRASG12D cell lines. It also exhibits prolonged PK/PD effects and excellent efficacy in mouse CDX models bearing KRASG12D tumors, highlighting its potential for the treatment of KRASG12D-driven tumors in clinical settings.