Document Report Card

ID: ALA2429834

Journal: J Med Chem

Title: Potent histone deacetylase inhibitors derived from 4-(aminomethyl)-N-hydroxybenzamide with high selectivity for the HDAC6 isoform.

Authors: Blackburn C, Barrett C, Chin J, Garcia K, Gigstad K, Gould A, Gutierrez J, Harrison S, Hoar K, Lynch C, Rowland RS, Tsu C, Ringeling J, Xu H.

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.

CiteXplore: 23964961

DOI: 10.1021/jm400385r