The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

中文翻译：

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5-（4-（异丙基磺酰基）苯基）-3-（3-（4-（（（甲基氨基）甲基）苯基）异恶唑-5-基）吡嗪-2-胺（VX-970，M6620）的合理设计：优化新型共济失调毛细血管扩张和Rad3相关（ATR）激酶抑制剂的分子内和分子间极性相互作用的研究。

DNA损伤反应（DDR）是一种DNA损伤监测和修复机制，可能会限制放射疗法和DNA破坏性化学疗法（通常用于癌症的治疗方式）的有效性。两种相关的激酶，共济失调的毛细血管扩张突变（ATM）和ATM和Rad3相关的激酶（ATR）一起作为DDR中的顶端蛋白，在面对可能致命的DNA损害时保持基因组稳定性和细胞存活。但是，受损的ATM信号传导是肿瘤细胞的共同特征，它更加依赖于ATR来介导DDR。在这种情况下，多项临床前研究表明，抑制ATR可以增强DNA破坏性化学疗法对许多癌细胞的毒性，而具有功能性ATM的健康组织可以耐受ATR抑制。因此，ATR代表了非常有吸引力的抗癌靶标。本文中我们描述了VX-970 / M6620的发现，VX-970 / M6620是第一种进入临床研究的ATR抑制剂，它基于Charrier（J. Med。Chem。2011，54，2320-2330，DOI ：10.1021 / jm101488z）。