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
• Publication Date: 2019-03-06T17:59:58Z
• Authors: Leticia Toledo-Sh...; Perla Breccia; Roger Cachope; Jennifer R. Bate; Ivan Angulo-Herrera; Grant Wishart; Kim L. Matthews; Sarah L. Martin; Helen C. Cox; George McAllister; Stephen D. Penrose; Huw Vater; William Esmieu; Amanda Van de Poël; Rhea Van de Bospoort; Annelieke Strijbosch; Marieke Lamers; Philip Leonard; Rebecca E. Jarvis; Wesley Blackaby; Karen Barnes; Maria Eznarriaga; Simon Dowler; Graham D. Smith; David F. Fischer; Ovadia Lazari; Dawn Yates; Mark Rose; Sung-Wook Jang; Ignacio Muñoz-San...; Celia Dominguez
• Keywords: 0301 basic medicine; Ataxia Telangiectasia Mutated Proteins; Proof of Concept Study; Madin Darby Canine Kidney Cells; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Dogs; Huntington Disease; Neuroprotective Agents; Animals; Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular animal models Huntington's disease (HD), suggesting selective inhibition ATM could provide a novel clinical intervention to treat HD. Here, we describe development characterization inhibitor molecules enable vivo proof-of-concept studies HD models. Starting from previously reported inhibitors, aimed with few modifications increase brain exposure by decreasing P-glycoprotein liability while maintaining potency selectivity. report brain-penetrant inhibitors have robust pharmacodynamic (PD) effects consistent mouse an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages shows dose-dependent X-ray irradiation-induced KAP1 phosphorylation brain. Furthermore, compound protects against mHTT (Q73)-induced cytotoxicity cortical-striatal cell model