1. Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.
- Author
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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, and Dominguez C
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Animals, Disease Models, Animal, Dogs, Humans, Madin Darby Canine Kidney Cells, Mice, Neuroprotective Agents metabolism, Neuroprotective Agents pharmacokinetics, Proof of Concept Study, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Huntington Disease drug therapy, Neuroprotective Agents therapeutic use
- 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.
- Published
- 2019
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