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. Epub 2019 Mar 19.


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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Disease Models, Animal
  • Dogs
  • Humans
  • Huntington Disease / drug therapy*
  • Madin Darby Canine Kidney Cells
  • Mice
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / therapeutic use*
  • Proof of Concept Study


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Neuroprotective Agents
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins