Discovery of Novel 3‑Quinoline Carboxamides as Potent, Selective, and Orally Bioavailable Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase

A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)­ethyl]­amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)­pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)­ethyl]­amino}­quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.本研究发现并优化了一系列新型3-喹啉甲酰胺类化合物，作为共济失调毛细血管扩张突变（ataxia telangiectasia mutated, ATM）激酶的选择性抑制剂。从活性中等的高通量筛选（High-throughput screening, HTS）命中化合物（化合物4）出发，我们鉴定得到了6-[6-(甲氧基甲基)-3-吡啶基]-4-{[(1R)-1-(四氢-2H-吡喃-4-基)乙基]氨基}-3-喹啉甲酰胺（化合物72）与7-氟-6-[6-(甲氧基甲基)吡啶-3-基]-4-{[(1S)-1-(1-甲基-1H-吡唑-3-基)乙基]氨基}喹啉-3-甲酰胺（化合物74）等强效且高选择性的ATM抑制剂，这类化合物整体具备适配口服给药的吸收、分布、代谢、排泄（Absorption, Distribution, Metabolism, Excretion, ADME）特性。化合物72与74是用于体内探究ATM抑制作用的优质口服工具化合物。在疾病相关模型中，联合使用该类抑制剂与DNA双链断裂（Double-strand break, DSB）诱导剂伊立替康可观测到治疗效应。