Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket

• Published in: Journal of structural biology Vol. 195; no. 3; pp. 373 - 378
• Main Authors: Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, Cole, Kathryn E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2016; Elsevier
• Subjects: AutoDock Vina; BASIC BIOLOGICAL SCIENCES; Catalytic Domain; Crystallography, X-Ray; Histone deacetylase 8; Histone deacetylase inhibitors (HDACi); Histone Deacetylase Inhibitors - chemistry; Histone Deacetylases - chemistry; Humans; Hydroxamic acids; Hydroxamic Acids - chemistry; Isoenzymes - chemistry; Molecular Docking Simulation; Protein Binding; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - chemistry; Histone deacetylase inhibitors (HDACi); Hydroxamic acids; Histone deacetylase 8; AutoDock Vina
• ISSN: 1047-8477; 1095-8657
• DOI: 10.1016/j.jsb.2016.06.023

Histone deacetylases (HDACs) catalyze the hydrolysis of acetylated lysine side chains in histone and non-histone proteins, and play a critical role in the regulation of many biological processes, including cell differentiation, proliferation, senescence, and apoptosis. Aberrant HDAC activity is associated with cancer, making these enzymes important targets for drug design. In general, HDAC inhibitors (HDACi) block the proliferation of tumor cells by inducing cell differentiation, cell cycle arrest, and/or apoptosis, and comprise some of the leading therapies in cancer treatments. To date, four HDACi have been FDA approved for the treatment of cancers: suberoylanilide hydroxamic acid (SAHA, Vorinostat, Zolinza®), romidepsin (FK228, Istodax®), belinostat (Beleodaq®), and panobinostat (Farydak®). Most current inhibitors are pan-HDACi, and non-selectively target a number of HDAC isoforms. Six previously reported HDACi were rationally designed, however, to target a unique sub-pocket found only in HDAC8. While these inhibitors were indeed potent against HDAC8, and even demonstrated specificity for HDAC8 over HDACs 1 and 6, there were no structural data to confirm the mode of binding. Here we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98Å resolution. We also describe the use of molecular docking studies to explore the binding interactions of the other 5 related HDACi. Our studies confirm that the HDACi induce the formation of and bind in the HDAC8-specific subpocket, offering insights into isoform-specific inhibition.