Abstract
KRAS, a frequently mutated oncogene, has been challenging to target therapeutically. Although covalent inhibitors like sotorasib against KRASG12C 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 KRASG12C, designed by incorporating an acrylamide warhead into the MRTX849 scaffold. It induces potent and sustained degradation of KRASG12C 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 KRASG12C-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.
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The Proteomics raw data have been deposited in a ProteomeXchange partner repository under PXD067337 and PXD072213. Source Data including uncropped and unprocessed scans of all blots and gels, reported means/averages in box plots, bar charts, and tables, including all quantified replicates are provided with this paper as a Source Data file.
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Acknowledgements
This work was supported by funds from Natural Science Foundation of China (22377033, 22377037, 22577038, 82473109), the Science and Technology Program of Guangdong Province (2023B1515120023, 2025A0505080018, 2024A1515013002, 2023A0505050149), Guangdong Basic and Applied Basic Research Foundation (2023B1515040016, 2025A1515012357, 2024A1515013266, 2026B1515020070). Science and Technology Project in Guangzhou (202102070001). Huizhou-Hong Kong-Macao Cooperation Development Fund (2025EQ010043). The authors sincerely thank to everyone who made scientific contributions to this work.
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Conception: J.D., S.S., L.H., F.X., W.H., C.H., Z.Z., T.L., Y.T., and Z.L. Experimental design and execution: J.D., S.S., L.H., F.X., W.H., C.H., Z.Z., T.L., Y.T., and Z.L. Data analysis, interpretation, and generation of figures: J.D., S.S., L.H., F.X., C.H., Z.Z., T.L., Y.T., and Z.L. Authored, edited and substantively revised the manuscript: J.D., S.S., L.H., F.X., T.L., Y.T., and Z.L.
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Deng, J., Shen, S., Huang, L. et al. Small-molecule degraders for oncogenic KRASG12C and pan-KRAS mutations. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71093-9
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DOI: https://doi.org/10.1038/s41467-026-71093-9
