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

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Author information

Affiliations

  • 1. CHDI Management/CHDI Foundation , 6080 Center Drive , Los Angeles , California 90045 , United States.
      Authors
    • Toledo-Sherman L 1
    • Cachope R 1
    • McAllister G 1
    • Rose M 1
    • Jang SW 1
    • Muñoz-Sanjuan I 1
    • Dominguez C 1
    (7 authors)
  • 2. Charles River , Chesterford Research Park , Saffron Walden CB10 1XL , U.K.
      Authors
    • Breccia P 2
    • Bate JR 2
    • Angulo-Herrera I 2
    • Wishart G 2
    • Matthews KL 2
    • Martin SL 2
    • Cox HC 2
    • Penrose SD 2
    • Vater H 2
    • Esmieu W 2
    • Van de Poël A 2
    • Lamers M 2
    • Leonard P 2
    • Jarvis RE 2
    • Blackaby W 2
    • Barnes K 2
    • Eznarriaga M 2
    • Dowler S 2
    • Smith GD 2
    • Fischer DF 2
    • Lazari O 2
    • Yates D 2
    (22 authors)
  • 3. Charles River , Leiden 2333 CR , Netherlands.
      Authors
    • Van de Bospoort R 3
    • Strijbosch A 3
    (2 authors)

ORCIDs linked to this article

Journal of Medicinal Chemistry, 19 Mar 2019, 62(6):2988-3008
https://doi.org/10.1021/acs.jmedchem.8b01819 PMID: 30840447 

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.

Full text links 

Read article at publisher's site: https://doi.org/10.1021/acs.jmedchem.8b01819

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