title: Inhibition of the function of class IIa HDACs by blocking their interaction with MEF2.
abstract: Enzymes that modify the epigenetic status of cells provide attractive targets for therapy in various diseases. The therapeutic development of epigenetic modulators, however, has been largely limited to direct targeting of catalytic active site conserved across multiple members of an enzyme family, which complicates mechanistic studies and drug development. Class IIa histone deacetylases (HDACs) are a group of epigenetic enzymes that depends on interaction with Myocyte Enhancer Factor-2 (MEF2) for their recruitment to specific genomic loci. Targeting this interaction presents an alternative approach to inhibiting this class of HDACs. We have used structural and functional approaches to identify and characterize a group of small molecules that indirectly target class IIa HDACs by blocking their interaction with MEF2 on DNA.Weused X-ray crystallography and (19)F NMRto show that these compounds directly bind to MEF2. We have also shown that the small molecules blocked the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of those targets. These compounds can be used as tools to study MEF2 and class IIa HDACs in vivo and as leads for drug development.
authors.affiliation: Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. jayathil@usc.edu
authors.forename: Nimanthi
authors.initials: N
authors.lastname: Jayathilaka
authors.forename: Aidong
authors.initials: A
authors.lastname: Han
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Gaffney
authors.forename: Raja
authors.initials: R
authors.lastname: Dey
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Jarusiewicz
authors.forename: Kaori
authors.initials: K
authors.lastname: Noridomi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Philips
authors.forename: Xiao
authors.initials: X
authors.lastname: Lei
authors.forename: Ju
authors.initials: J
authors.lastname: He
authors.forename: Jun
authors.initials: J
authors.lastname: Ye
authors.forename: Tao
authors.initials: T
authors.lastname: Gao
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
mesh_terms: D000813:Anilides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000737:chemistry; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D064326:MEF2 Transcription Factors; D008958:Models, Molecular; D018006:Myogenic Regulatory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000813:Anilides; D056572:Histone Deacetylase Inhibitors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; C514580:N1-(2-aminophenyl)-N8-phenyloctanediamide; D004247:DNA; D006655:Histone Deacetylases