Discovery of highly potent and selective KRAS degraders by VHL-recruiting PROTACs for the treatment of tumors with KRAS-Mutation.

Although several covalent KRAS inhibitors have made great progress in the treatment of KRAS-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRAS Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRAS-dependent cancer cells growth with nanomolar IC and DC values, and ＞ 95 % maximum degradation (D). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRAS: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRAS degradation exhibited advantages in overcoming adaptive KRAS feedback resistance over KRAS inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRAS-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRAS-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.