KRAS^G12D selective VHL-PROTAC with sparing KRAS^WT and other KRAS mutants

KRAS^G12D is the most prevalent KRAS mutant in various cancers. We report the KRAS^G12D selective PROTAC, CH091138 (6), identified through SAR studies. 6 selectively degrades exogenous and endogenous KRAS^G12D but not KRAS^WT or other KRAS mutants. Furthermore, global proteomic analysis shows that KRAS is most significantly downregulated in AsPC-1 cells. Mechanistic studies reveal that the degradation depends on the VHL-mediated ubiquitin-proteasome system. The binding site of 6 was identified by NMR studies, and docking studies explain 6-mediated interaction between KRAS^G12D and VHL leads to KRAS^G12D selectivity. 6 suppresses the proliferation of AsPC-1 cells and the growth of colon cancer patient-derived organoids (PDOs) harboring KRAS^G12D but not PDOs with KRAS^WT. Notably, 6 reduces tumor growth in an AsPC-1 xenograft mouse model. Collectively, we report KRAS^G12D selective PROTAC and propose potential hypotheses for the selectivity. Also, our study reveals that PROTAC-mediated degradation of KRAS^G12D is an attractive anti-cancer strategy.