Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent
Discovery and Characterization of AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Kinase with Application as an Anticancer Agent
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DOI：
10.1021/acs.jmedchem.8b01187
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发表时间：
2018-11-22
影响因子：
7.3
通讯作者：
Jewsbury, Philip J.
中科院分区：
文献类型：
--
作者：
Foote, Kevin M.;Nissink, J. Willem M.;Jewsbury, Philip J.
激酶共济失调毛细血管扩张突变和rad 3相关（ATR）是DNA损伤反应和顶端激酶的关键调节因子，其协调修复停滞的复制叉（复制应激）和相关DNA双链断裂的细胞过程。在替代途径活性较低的情况下，ATR介导的修复途径抑制预期可通过增加复制应激来帮助临床应答。在这里，我们描述了临床候选药物2（AZD 6738）的开发，AZD 6738是一种有效的选择性亚砜亚胺吗啉嘧啶ATR抑制剂，具有优异的临床前理化和药代动力学（PK）特征。从先前描述的抑制剂1（AZ 20）开始，开发了化合物2，其改善了水溶性并消除了CYP 3A 4时间依赖性抑制。临床候选药物2具有良好的人体PK，适合每日给药一次或两次，并在中等剂量下实现生物学有效暴露。化合物2目前正在多个I/II期试验中作为抗癌剂进行测试。
The kinase ataxia telangiectasia mutated and rad3 related (ATR) is a key regulator of the DNA-damage response and the apical kinase which orchestrates the cellular processes that repair stalled replication forks (replication stress) and associated DNA double-strand breaks. Inhibition of repair pathways mediated by ATR in a context where alternative pathways are less active is expected to aid clinical response by increasing replication stress. Here we describe the development of the clinical candidate 2 (AZD6738), a potent and selective sulfoximine morpholinopyrimidine ATR inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics. Compound 2 was developed improving aqueous solubility and eliminating CYP3A4 time-dependent inhibition starting from the earlier described inhibitor 1 (AZ20). The clinical candidate 2 has favorable human PK suitable for once or twice daily dosing and achieves biologically effective exposure at moderate doses. Compound 2 is currently being tested in multiple phase I/II trials as an anticancer agent.