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ID: ALA4680114
Journal: J Med Chem
Title: Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.
Authors: Toledo-Sherman L,Breccia P,Cachope R,Bate JR,Angulo-Herrera I,Wishart G,Matthews KL,Martin SL,Cox HC,McAllister G,Penrose SD,Vater H,Esmieu W,Van de Poël A,Van de Bospoort R,Strijbosch A,Lamers M,Leonard P,Jarvis RE,Blackaby W,Barnes K,Eznarriaga M,Dowler S,Smith GD,Fischer DF,Lazari O,Yates D,Rose M,Jang SW,Muñoz-Sanjuan I,Dominguez C
Abstract: 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.
CiteXplore: 30840447