title: Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N-hydroxybenzamide with high selectivity for the HDAC6 isoform.
abstract: A screen for HDAC6 inhibitors identified acyl derivatives of 4-(aminomethyl)-N-hydroxybenzamide as potent leads with unexpected selectivity over the other subtypes. We designed and synthesized constrained heterocyclic analogues such as tetrahydroisoquinolines that show further enhanced HDAC6 selectivity and inhibitory activity in cellular assays. Selectivity may be attributed to the benzylic spacer more effectively accessing the wider channel of HDAC6 compared to other HDAC subtypes as well as hydrophobic capping groups interacting with the protein surface near the rim of the active site.
authors: Discovery, Millennium Pharmaceuticals, Inc. , 40 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
authors: Christopher
authors: C
authors: Blackburn
authors: Cynthia
authors: C
authors: Barrett
authors: Janice
authors: J
authors: Chin
authors: Kris
authors: K
authors: Garcia
authors: Kenneth
authors: K
authors: Gigstad
authors: Alexandra
authors: A
authors: Gould
authors: Juan
authors: J
authors: Gutierrez
authors: Sean
authors: S
authors: Harrison
authors: Kara
authors: K
authors: Hoar
authors: Chrissie
authors: C
authors: Lynch
authors: R Scott
authors: RS
authors: Rowland
authors: Chris
authors: C
authors: Tsu
authors: John
authors: J
authors: Ringeling
authors: He
authors: H
authors: Xu
mesh_terms: D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C037689:benzamide; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases