发现一系列3-噌啉甲酰胺类化合物作为口服生物可利用的、高效且选择性的ATM抑制剂。
Discovery of a Series of 3-Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors.
作者信息
Barlaam Bernard, Cadogan Elaine, Campbell Andrew, Colclough Nicola, Dishington Allan, Durant Stephen, Goldberg Kristin, Hassall Lorraine A, Hughes Gareth D, MacFaul Philip A, McGuire Thomas M, Pass Martin, Patel Anil, Pearson Stuart, Petersen Jens, Pike Kurt G, Robb Graeme, Stratton Natalie, Xin Guohong, Zhai Baochang
机构信息
Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, U.K.
Oncology, IMED Biotech Unit, AstraZeneca, Macclesfield, U.K.
出版信息
ACS Med Chem Lett. 2018 Jul 13;9(8):809-814. doi: 10.1021/acsmedchemlett.8b00200. eCollection 2018 Aug 9.
Abstract
We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound , a highly potent ATM inhibitor (ATM cell IC 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. , in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound was selected for preclinical evaluation alongside AZD0156.
摘要
我们报告发现了一系列新型的3-噌啉甲酰胺，它们是高效且选择性的共济失调毛细血管扩张症突变（ATM）激酶抑制剂。围绕效力和物理化学性质（尤其是通透性）对该系列进行优化，从而鉴定出化合物，它是一种高效的ATM抑制剂（ATM细胞IC50为0.0028 μM），具有出色的激酶选择性以及良好的物理化学和药代动力学性质。化合物与伊立替康联合使用时，在SW620结直肠癌异种移植模型中显示出肿瘤消退，抑制效果优于单独使用伊立替康。化合物与AZD0156一起被选用于临床前评估。
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