Publication date: Mar 06, 2019
Genetic and pharmacological evidence indicates that 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 (P-gp) 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 mouse brain and an understood pharmacokinetic/pharmacodynamic (PK/PD) relationship. Compound 17, engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.
Toledo-Sherman, L.M., Breccia, P., Cachope, R., , Bate, , Angulo-Herrera, Wishart, G., Matthews, K.L., Martin, S.L., Cox, H.C., McAllister, G., Penrose, S.D., Vater, H., Esmieu, W., Van de Po”el, A., Van de Bospoort, R., Strijbosch, A., Lamers, M.B.A.C., Leonard, P.M., Jarvis, R., Blackaby, W., Barnes, K., Eznarriaga, M., Dowler, S., Smith, G.D., Fischer, D., Lazari, O., Yates, D., Rose, M., Jang, S.W., , Mu~noz-Sanjuan, and Dominguez, C. “Optimization of potent and selective Ataxia Telangiectasia Mutated (ATM) inhibitors suitable for a proof-of-concept study in Huntington’s disease models”. 06382. 2019 J Med Chem.
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