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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

DOI: 10.1021/acs.jmedchem.8b01819 DOI Help

Authors: Leticia Toledo-sherman (CHDI Management/CHDI Foundation) , Perla Breccia (Charles River) , Roger Cachope (CHDI Management/CHDI Foundation) , Jennifer R. Bate (Charles River) , Ivan Angulo-herrera (Charles River) , Grant Wishart (Charles River) , Kim L. Matthews (Charles River) , Sarah L. Martin (Charles River) , Helen C. Cox (Charles River) , George Mcallister (CHDI Management/CHDI Foundation) , Stephen D. Penrose (Charles River) , Huw Vater (Charles River) , William Esmieu (Charles River) , Amanda Van De Poël (Charles River) , Rhea Van De Bospoort (Charles River) , Annelieke Strijbosch (Charles River) , Marieke Lamers (Charles River) , Philip Leonard (Charles River) , Rebecca E. Jarvis (Charles River) , Wesley Blackaby (Charles River) , Karen Barnes (Charles River) , Maria Eznarriaga (Charles River) , Simon Dowler (Charles River) , Graham D. Smith (Charles River) , David F. Fischer (Charles River) , Ovadia Lazari (Charles River) , Dawn Yates (Charles River) , Mark Rose (CHDI Management/CHDI Foundation) , Sung-wook Jang (CHDI Management/CHDI Foundation) , Ignacio Muñoz-sanjuan (CHDI Management/CHDI Foundation) , Celia Dominguez (CHDI Management/CHDI Foundation)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 14629

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography