KRASG12D selective VHL-PROTAC with sparing KRASWT and other KRAS mutants

Abstract

KRASG12D is the most prevalent KRAS mutant in various cancers. We report the KRASG12D selective PROTAC, CH091138 (6), identified through SAR studies. 6 selectively degrades exogenous and endogenous KRASG12D but not KRASWT 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 KRASG12D and VHL leads to KRASG12D selectivity. 6 suppresses the proliferation of AsPC-1 cells and the growth of colon cancer patient-derived organoids (PDOs) harboring KRASG12D but not PDOs with KRASWT. Notably, 6 reduces tumor growth in an AsPC-1 xenograft mouse model. Collectively, we report KRASG12D selective PROTAC and propose potential hypotheses for the selectivity. Also, our study reveals that PROTAC-mediated degradation of KRASG12D is an attractive anti-cancer strategy.