DNA修复酶MTH1抑制剂研究进展

Research Advances in Inhibitors of DNA Repair Enzyme MTH1

MTH1是一种DNA氧化损伤修复酶,主要负责"清理"核苷酸池中氧化损伤的脱氧核苷三磷酸(d NTPs),以防其掺入DNA复制中而造成碱基错配。研究表明,MTH1与肿瘤细胞的生存密切相关,而正常细胞的生长与存活则不依赖于MTH1。所以,以MTH1为靶点开展抗肿瘤新药研发,已逐渐受到人们的关注。抑制MTH1,为肿瘤治疗开辟了一条新途经。简介MTH1的结构和功能及其与肿瘤的关联,着重对近年来MTH1抑制剂的发现过程和研究进展作一综述,探究小分子MTH1抑制剂与MTH1蛋白的作用模式,为MTH1抑制剂的设计提供思路。

MTH1 is an oxidative DNA damage repair enzyme that is mainly responsible for the ＂clean-up＂ of oxidized d NTPs in nucleotide pools to prevent incorporation of damaged bases during DNA replication. It has been suggested that MTH1 is closely related to the survival of tumor cells, however, the growth and survival of normal cells do not depend on MTH1. Therefore, the development of new antitumor drugs targeting MTH1 has been paid more and more attention. MTH1 inhibition embodies a new approach for tumor therapy. In this paper, the structure and function of MTH1 and its association with tumors were introduced, especially the discovery and reseach advances in MTH1 inhibitors in recent years were reviewed and the interaction modes of small-molecule MTH1 inhibitors with MTH1 protein were explored, so as to provide some strategies for the design of MTH1 inhibitors.