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Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor

DOI: 10.1016/j.bmcl.2018.11.009 DOI Help

Authors: Christopher A. Luckhurst (Charles River Discovery) , Omar Aziz (Charles River Discovery) , Vahri Beaumont (CHDI Management/CHDI Foundation Inc.) , Roland W. Bürli (Charles River Discovery) , Perla Breccia (Charles River Discovery) , Michel C. Maillard (CHDI Management/CHDI Foundation Inc.) , Alan F. Haughan (Charles River Discovery) , Marieke Lamers (Charles River Discovery) , Phil Leonard (Charles River Discovery) , Kim L. Matthews (Charles River Discovery) , Gilles Raphy (Charles River Discovery) , Andrew J. Stott (Charles River Discovery) , Ignacio Munoz-sanjuan (CHDI Management/CHDI Foundation Inc.) , Beth Thomas (Charles River Discovery) , Michael Wall (Charles River Discovery) , Grant Wishart (Charles River Discovery) , Dawn Yates (Charles River Discovery) , Celia Dominguez (CHDI Management/CHDI Foundation Inc.)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Bioorganic & Medicinal Chemistry Letters

State: Published (Approved)
Published: November 2018

Abstract: We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.

Journal Keywords: CHDI-390576; Hydroxamic acid; CNS-penetrant; HDAC4 inhibition; Class IIa HDAC inhibitor

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


Instruments: I04-Macromolecular Crystallography