Department of Respiratory and Critical Care Medicine and Targeted Tracer Research and Development Laboratory and Institute of Respiratory Health and State Key Laboratory of Respiratory Health and Multimorbidity and Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, Sichuan China.
Department of Dermatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan China.
J Med Chem. 2024 Sep 12;67(17):14742-14767. doi: 10.1021/acs.jmedchem.4c01064. Epub 2024 Aug 16.
The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure-activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.
蛋白激酶共济失调毛细血管扩张突变（ATM）是磷脂酰肌醇 3-激酶相关激酶（PIKK）家族的组成部分，对多种细胞过程，特别是双链 DNA 断裂（DSB）和应激反应的信号转导，发挥着关键影响。ATM 的失调与癌症和其他疾病（如神经退行性疾病）的发病机制有关。因此，ATM 被认为是一系列疾病中潜在治疗干预的有前途的候选物。目前，虽然 ATM 小分子抑制剂尚未商业化，但各种选择性抑制剂已进入临床研究阶段。具体而言，AZD1390、WSD0628、SYH2051 和 ZN-B-2262 分别在针对多形性胶质母细胞瘤和晚期实体瘤的临床研究中进行研究。在本观点中，我们总结了 ATM 的结构、生物学功能和疾病相关性。随后，我们专注于 ATM 抑制剂的设计理念和结构-活性关系（SAR），阐述了开发更有效的 ATM 靶向抑制剂的潜在途径。
