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<p>KRAS, a frequently mutated oncogene, has been challenging to target therapeutically. Although covalent inhibitors like sotorasib against KRAS<sup>G12C</sup> 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<sup>G12C</sup>, designed by incorporating an acrylamide warhead into the MRTX849 scaffold. It induces potent and sustained degradation of KRAS<sup>G12C</sup> 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<sup>G12C</sup>-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.</p>

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Small-molecule degraders for oncogenic KRASG12C and pan-KRAS mutations

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月26日

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  • Jianxiong Deng,
  • Shujun Shen,
  • Lei Huang,
  • Fang Xu,
  • Weizhen Huang,
  • Chaoming Huang,
  • Zhang Zhang,
  • Tongzheng Liu,
  • Yi Tan,
  • Zhengqiu Li

摘要

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.