A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers

KRAS is the most frequently mutated oncogene in human cancers, yet to date, only KRASG12C inhibitors have been approved by the FDA. Small-molecule inhibitors targeting the larger number of tumors expressing prevalent KRAS mutants remain an unmet medical need. Here, we report a highly potent pan-KRAS inhibitor, MCB-294, that selectively inactivates KRAS while sparing NRAS and HRAS. Biochemical studies show that MCB-294 binds to and inhibits wild-t cells and remodel the tumor microenvironment by boosting T cell-mediated anti-tumor immunity. Taken together, our findings demonstrate a successful and feasible strategy for targeting pan-KRAS to impair multifacete c efficacy against the growth of KRAS-mutant tumors, and prolongs mouse survival by rectifying unfavorable alterations in the KRAS-ERK-dependent signature. By employing an MCB-294 derivative as a KRAS binder, we further identify a VHL-based pan-KRAS degrader, MCB-36, that efficiently degrades KRAS in vitro and in vivo through the ubiquitin-proteasome system. Notably, MCB-294 and MCB-36 effectively kill KRASG12C inhibitor-resistant cells and remodel the tumor microenvironment by boosting T cell-mediated anti-tumor immunity. Taken together, our findings demonstrate a successful and feasible strategy for targeting pan-KRAS to impair multifaceted features of KRAS-driven tumors.