title: Discovery of the first histone deacetylase 6/8 dual inhibitors.
abstract: We disclose the first small molecule histone deacetylase (HDAC) inhibitor (3, BRD73954) capable of potently and selectively inhibiting both HDAC6 and HDAC8 despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our data demonstrate that meta substituents of phenyl hydroxamic acids are readily accommodated upon binding to HDAC6 and, furthermore, are necessary for the potent inhibition of HDAC8.
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Olson
authors.forename: Florence F
authors.initials: FF
authors.lastname: Wagner
authors.forename: Taner
authors.initials: T
authors.lastname: Kaya
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Gale
authors.forename: Nadia
authors.initials: N
authors.lastname: Aidoud
authors.forename: Emeline L
authors.initials: EL
authors.lastname: Davoine
authors.forename: Fanny
authors.initials: F
authors.lastname: Lazzaro
authors.forename: Michel
authors.initials: M
authors.lastname: Weïwer
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.forename: Edward B
authors.initials: EB
authors.lastname: Holson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C582932:BRD73954; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010795:Phthalic Acids; D012097:Repressor Proteins; C433811:HDAC6 protein, human; C409470:HDAC8 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases