skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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

Journal Article · · Journal of Structural Biology
 [1];  [2];  [1];  [3];  [1]
  1. Christopher Newport Univ., Newport News, VA (United States)
  2. Ithaca College, NY (United States)
  3. Argonne National Lab. (ANL), Argonne, IL (United States)
+ Show Author Affiliations

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. In this paper we report the X-ray crystal structure of Compound 6 complexed with HDAC8 to 1.98 Å 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Office of Research Infrastructure Programs (ORIP); USDOE Office of Science (SC)
Grant/Contract Number:
P41 GM103403; S10 RR029205; AC02-06CH11357
OSTI ID:
1324808
Alternate ID(s):
OSTI ID: 1359493
Journal Information:
Journal of Structural Biology, Vol. 195, Issue 3; ISSN 1047-8477
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 50 works
Citation information provided by
Web of Science

References (26)

PHENIX : building new software for automated crystallographic structure determination journal October 2002
Isoform-specific histone deacetylase inhibitors: The next step? journal August 2009
Histone Deacetylases 5 and 9 Govern Responsiveness of the Heart to a Subset of Stress Signals and Play Redundant Roles in Heart Development journal October 2004
Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases journal August 2011
Histone deacetylases (HDACs): characterization of the classical HDAC family journal March 2003
Structural Studies of Human Histone Deacetylase 8 and Its Site-Specific Variants Complexed with Substrate and Inhibitors † , ‡ journal December 2008
Structures of Metal-Substituted Human Histone Deacetylase 8 Provide Mechanistic Inferences on Biological Function, journal June 2010
Coot model-building tools for molecular graphics journal November 2004
FDA Approves New Agent for Multiple Myeloma journal March 2015
Histone deacetylases and cancer journal August 2007
The many roles of histone deacetylases in development and physiology: implications for disease and therapy journal January 2009
Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis journal March 2016
Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8 journal March 2015
Suberoylanilide Hydroxamic Acid as a Potential Therapeutic Agent for Human Breast Cancer Treatment journal October 2000
Discovery of Inhibitors of Schistosoma mansoni HDAC8 by Combining Homology Modeling, Virtual Screening, and in Vitro Validation
  • Kannan, Srinivasaraghavan; Melesina, Jelena; Hauser, Alexander-Thomas
  • Journal of Chemical Information and Modeling, Vol. 54, Issue 10 https://doi.org/10.1021/ci5004653
journal September 2014
Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors journal May 2007
FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma journal March 2015
FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma journal October 2007
Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni journal September 2013
Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice journal November 2008
Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors journal December 2013
Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation journal February 2015
Exploring the Potential binding Sites of Some Known HDAC Inhibitors on Some HDAC8 Conformers by Docking Studies journal June 2014
Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases journal July 2004
Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor journal October 2004
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex journal August 2007

Cited By (11)

A Genetically Encoded, Phage‐Displayed Cyclic‐Peptide Library journal September 2019
A Genetically Encoded, Phage‐Displayed Cyclic‐Peptide Library journal September 2019
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing journal April 2019
Molecular dynamics study of HDAC8-largazole analogues co-crystals for designing potential anticancer compounds journal April 2019
Examining the stability of binding modes of the co-crystallized inhibitors of human HDAC8 by molecular dynamics simulation journal May 2019
Determination of the binding mechanism of histone deacetylase inhibitors journal December 2018
Structure–activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery journal December 2017
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing text January 2019
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing text January 2019
HDAC8 functions in spindle assembly during mouse oocyte meiosis journal February 2017
Synthesis and Preliminary Biological Evaluation of Two Fluoroolefin Analogs of Largazole Inspired by the Structural Similarity of the Side Chain Unit in Psammaplin A journal June 2019

Similar Records

Structural Basis of the Antiproliferative Activity of Largazole a Depsipeptide Inhibitor of the Histone Deacetylases
Journal Article · Sat Dec 31 00:00:00 EST 2011 · Journal of the American Chemical Society · OSTI ID:1324808
+2 more
4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation
Journal Article · Sat Aug 15 00:00:00 EDT 2015 · Experimental Cell Research · OSTI ID:1324808
+1 more
Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis
Journal Article · Fri Jul 19 00:00:00 EDT 2013 · Biochemical and Biophysical Research Communications · OSTI ID:1324808
+2 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Histone deacetylase 8
Histone deacetylase inhibitors (HDACi)
Hydroxamic acids
AutoDock Vina