Structural Biasing Elements for In-Cell Histone Deacetylase Paralog Selectivity

• Published in: Journal of the American Chemical Society Vol. 125; no. 19; pp. 5586 - 5587
• Main Authors: Wong, Jason C, Hong, Roger, Schreiber, Stuart L
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 14-05-2003
• Subjects: Analytical chemistry; Anilides - chemistry; Anilides - pharmacology; Chemistry; Dioxanes - chemical synthesis; Dioxanes - chemistry; Dioxanes - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Histone Deacetylase Inhibitors; Histone Deacetylases - metabolism; Humans; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Miscellaneous; Structure-Activity Relationship; Analytical chemistry; Biochemistry
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja0341440

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.