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A small GTPase encoded by Kirsten rat sarcoma viral proto oncogene (RAS) is a key regulatory protein in multiple cellular signaling pathways. The mutation of glycine to cysteine (G12C) at position 12 often leads to abnormal activation of cellular pathways, which plays an important role in the occurrence and development of tumors. Small molecule covalent inhibitors targeting KRAS^G12C protein can directly inhibit the abnormal activation of cellular pathways caused by KRAS^G12C mutation. In this paper, the structure and function of KRAS protein, as well as the research and development progress, challenges and possible solutions of covalent inhibitors of its G12C mutant are reviewed. The development direction of (K) RAS inhibitors in the future is prospected in order to provide a useful reference for the research and development of such inhibitors.

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Kirsten大鼠肉瘤病毒癌基因（KRAS）编码的一种小GTP酶是多条细胞信号通路中关键的调控蛋白，其12位甘氨酸突变为半胱氨酸（G12C）常导致细胞通路异常活化，这在肿瘤的发生发展中起着重要作用，而靶向KRAS^G12C蛋白的小分子共价抑制剂能够直接抑制由KRAS^G12C突变造成的细胞通路异常活化。本文就KRAS蛋白结构和功能及其G12C突变体的共价抑制剂的研发进展、面临的挑战及可能的解决方法进行综述，并对未来KRAS抑制剂的发展方向进行展望，旨在为该类抑制剂的研发提供有益的参考。

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韩忝甫，男，硕士研究生，主要从事药物化学研究工作。 E-mail: htf1993hm@163.com。

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韩忝甫，男，硕士研究生，主要从事药物化学研究工作。 E-mail: htf1993hm@163.com。

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