CHDI Management/CHDI Foundation , 6080 Center Drive , Los Angeles , California 90045 , United States.
Charles River , Chesterford Research Park , Saffron Walden CB10 1XL , U.K.
J Med Chem. 2019 Mar 28;62(6):2988-3008. doi: 10.1021/acs.jmedchem.8b01819. Epub 2019 Mar 19.
Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.
遗传和药理学证据表明，降低共济失调毛细血管扩张突变（ATM）激酶活性可以改善亨廷顿病（HD）的细胞和动物模型中的突变亨廷顿（mHTT）毒性，这表明选择性抑制 ATM 可能为治疗 HD 提供一种新的临床干预措施。在这里，我们描述了 ATM 抑制剂分子的开发和表征，以在 HD 动物模型中进行体内概念验证研究。从先前报道的 ATM 抑制剂开始，我们的目标是通过减少 P-糖蛋白的易感性，同时保持效力和选择性，进行少量修饰以增加脑暴露。在这里，我们报告了具有脑穿透性的 ATM 抑制剂，它们在小鼠脑中具有与 ATM 激酶抑制一致的强大药效学（PD）作用，并且具有可理解的药代动力学/药效学（PK/PD）关系。化合物 17 与 ATM 激酶结合，并在小鼠脑中显示出对 X 射线照射诱导的 KAP1 磷酸化的强大剂量依赖性抑制作用。此外，化合物 17 可防止 mHTT（Q73）诱导的 HD 皮质纹状体细胞模型中的细胞毒性。
