Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective,Journal of Medicinal Chemistry

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Small Molecular Inhibitors That Target ATM for Drug Discovery: Current Research and Potential Prospective
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-16 , DOI: 10.1021/acs.jmedchem.4c01064
Chunlin Qian ₁ , Xiaoxue Li ₂ , Jifa Zhang _{1,

3} , Yuxi Wang _{1,

3}

Affiliation

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.

中文翻译：

以 ATM 为目标的小分子抑制剂用于药物发现：当前研究和潜在前景

毛细血管扩张共济失调蛋白激酶突变 (ATM) 是磷脂酰肌醇 3 激酶相关激酶 (PIKK) 家族的组成部分，对多种细胞过程发挥关键影响，特别是双链 DNA 断裂 (DSB) 信号传导和应激反应。 ATM 失调与癌症和神经退行性疾病等其他疾病的发病机制有关。因此，ATM 被认为是对一系列疾病进行潜在治疗干预的有希望的候选者。目前，虽然ATM小分子抑制剂尚未商业化，但多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分别正在与多形性胶质母细胞瘤和晚期实体瘤相关的临床研究中进行研究。在本视角中，我们概括了 ATM 的结构、生物学功能和疾病相关性。随后，我们专注于 ATM 抑制剂的设计概念和构效关系 (SAR)，描绘出开发更有效的 ATM 靶向抑制剂的潜在途径。

更新日期：2024-08-16

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