Structural biasing elements for in-cell histone deacetylase paralog selectivity.
We use the structural dissection of two 1,3-dioxanes with in-cell histone deacetylase (HDAC) paralog selectivity to identify key elements for selective HDAC inhibitors. We demonstrate that o-aminoanilides are inactive toward HDAC6 while apparently inhibiting deacetylases that act upon histone substrates. This finding has important clinical implications for the development of HDAC inhibitor-based treatments that do not interfere with microtubule dynamics associated with HDAC6. We also show that suberoylanilide hydroxamic acid (SAHA) alone is a nonparalog-selective HDAC inhibitor and that the 1,3-dioxane diversity appended to SAHA is essential for HDAC6 paralog selectivity.
Department of Chemistry and Chemical Biology, Harvard Institute of Chemistry and Cell Biology, and the Howard Hughes Medical Institute, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
Jason C
JC
Wong
Roger
R
Hong
Stuart L
SL
Schreiber
D000813:Anilides / Q000737:chemistry / Q000494:pharmacology; D004146:Dioxanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000813:Anilides; D004146:Dioxanes; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C474316:tubacin; D006655:Histone Deacetylases