Small-molecule degraders for oncogenic KRASG12C and pan-KRAS mutations - PubMed
4 hours ago
- #protein degradation
- #cancer therapeutics
- #KRAS mutations
- DJX-A-KM is a small-molecule degrader designed for oncogenic KRASG12C by incorporating an acrylamide warhead into the MRTX849 scaffold.
- It induces potent and sustained degradation of KRASG12C both in cells and in vivo, mediated by the ubiquitin-proteasome system via covalent engagement with E3 ligase FBXO28 at cysteine 98.
- The degrader shows strong antiproliferation effects across multiple KRASG12C-mutant cancer models and provides a strategy for developing pan-KRAS degraders against broader KRAS mutations.
- The work highlights a blueprint for exploring E3 ligases in targeted protein degradation, offering a potential solution to overcome resistance limitations of covalent inhibitors like sotorasib.