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

  • J Med Chem. 2019 Mar 28;62(6):2988-3008. doi: 10.1021/acs.jmedchem.8b01819.
Leticia Toledo-Sherman  1 ,  Perla Breccia  2 ,  Roger Cachope  1 ,  Jennifer R Bate  2 ,  Ivan Angulo-Herrera  2 ,  Grant Wishart  2 ,  Kim L Matthews  2 ,  Sarah L Martin  2 ,  Helen C Cox  2 ,  George McAllister  1 ,  Stephen D Penrose  2 ,  Huw Vater  2 ,  William Esmieu  2 ,  Amanda Van de Poël  2 ,  Rhea Van de Bospoort  3 ,  Annelieke Strijbosch  3 ,  Marieke Lamers  2 ,  Philip Leonard  2 ,  Rebecca E Jarvis  2 ,  Wesley Blackaby  2 ,  Karen Barnes  2 ,  Maria Eznarriaga  2 ,  Simon Dowler  2 ,  Graham D Smith  2 ,  David F Fischer  2 ,  Ovadia Lazari  2 ,  Dawn Yates  2 ,  Mark Rose  1 ,  Sung-Wook Jang  1 ,  Ignacio Muñoz-Sanjuan  1 ,  Celia Dominguez  1
Affiliations
  • 1. CHDI Management/CHDI Foundation , 6080 Center Drive , Los Angeles , California 90045 , United States.
  • 2. Charles River , Chesterford Research Park , Saffron Walden CB10 1XL , U.K.
  • 3. Charles River , Leiden 2333 CR , Netherlands.
PMID: 30840447 DOI: 10.1021/acs.jmedchem.8b01819
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.