Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington’s Disease Models

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.