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Design, Synthesis, and Biological Evaluation of Potent and Selective Class IIa Histone Deacetylase (HDAC) Inhibitors as a Potential Therapy for Huntington’s Disease

DOI: 10.1021/jm4011884 DOI Help
PMID: 24261862 PMID Help

Authors: Roland W. Bürli (BioFocus) , Christopher A. Luckhurst (BioFocus) , Omar Aziz (BioFocus) , Kim L. Matthews (BioFocus) , Dawn Yates (BioFocus) , Kathy. A. Lyons (BioFocus) , Maria Beconi (CHDI Management/CHDI Foundation Inc) , George Mcallister (BioFocus) , Perla Breccia (BioFocus) , Andrew J. Stott (BioFocus) , Stephen D. Penrose (BioFocus) , Michael Wall (BioFocus) , Marieke Lamers (BioFocus) , Philip Leonard (BioFocus) , Ilka Müller (BioFocus) , Christine M. Richardson (BioFocus) , Rebecca Jarvis (BioFocus) , Liz Stones (BioFocus) , Samantha Hughes (BioFocus) , Celia Dominguez (CHDI Management/CHDI Foundation Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 56 (24) , PAGES 9934 - 9954

State: Published (Approved)
Published: December 2013

Abstract: Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington’s disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a “closed-loop” form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.

Journal Keywords: Dose-Response; Drug; Drug; Histone; Histone; Humans; Huntington; Isoenzymes; Male; Mice; Mice; Inbred; Microsomes; Liver; Models; Molecular; Structure-Activity Relationship

Subject Areas: Chemistry

Instruments: I04-Macromolecular Crystallography