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

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

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.

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