Design, synthesis and biological evaluation of KRAS^G12C-PROTACs

Several small-molecule covalent inhibitors of KRAS^G12C have made breakthrough progress in the treatment of KRAS mutant cancer. However, the clinical application of KRAS^G12C small-molecule inhibitors may be limited by adaptive resistance. Emerging PROTAC strategy can achieve complementary advantages with small molecule inhibitors and improve anti-tumor efficacy. Based on AMG-510, a series of novel KRAS^G12C-PROTACs were designed and synthesized. The protein degradation assay showed that PROTACs I-1, II-1, III-2 and IV-1 had binding and degradation ability to KRAS^G12C. III-2 and IV-1 showed potent inhibitory effect on downstream p-ERK and were more potent than AMG-510. Mechanistic studies demonstrated that PROTACs exerted degradation effects through the ubiquitin-proteasome pathway. Using cell lines sensitive to KRAS^G12C, anti-proliferative activities of compounds were assessed. PROTACs tested showed overall anti-proliferative activities. Besides,the structure-activity relationships (SARs) of KRAS^G12C-PROTACs were summarized. These results supported the use of the PROTAC strategy to degrade oncogene KRAS^G12C and provided clues for structural optimization of KRAS^G12C-PROTACs.