Small-molecule degraders for oncogenic KRAS^G12C and pan-KRAS mutations.

Abstract

KRAS, a frequently mutated oncogene, has been challenging to target therapeutically. Although covalent inhibitors like sotorasib against KRAS^G12C have been developed, their efficacy is often limited by acquired resistance. Targeted protein degradation offers a potential solution but has largely relied on large PROTAC molecules. Here, we report DJX-A-KM, a small-molecule degrader of KRAS^G12C, designed by incorporating an acrylamide warhead into the MRTX849 scaffold. It induces potent and sustained degradation of KRAS^G12C in cells and in vivo. Mechanistic investigation reveal that degradation is mediated by the ubiquitin-proteasome system, facilitated by covalent engagement with a E3 ligase, FBXO28, at cysteine 98. Antiproliferation assays demonstrate its potent inhibitory effects across multiple KRAS^G12C-mutant cancer models. This strategy also enables the development of pan-KRAS degraders against a broader spectrum of KRAS mutations. Our work presents a small-molecule degrader recruiting FBXO28 and provides a blueprint for exploring E3 ligases in protein degradation.