Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket
Abstract
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 interactionsmore »
- Authors:
-
- Christopher Newport Univ., Newport News, VA (United States)
- Ithaca College, NY (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); Office of Research Infrastructure Programs (ORIP); USDOE Office of Science (SC)
- OSTI Identifier:
- 1324808
- Alternate Identifier(s):
- OSTI ID: 1359493
- Grant/Contract Number:
- P41 GM103403; S10 RR029205; AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Structural Biology
- Additional Journal Information:
- Journal Volume: 195; Journal Issue: 3; Journal ID: ISSN 1047-8477
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Histone deacetylase 8; Histone deacetylase inhibitors (HDACi); Hydroxamic acids; AutoDock Vina
Citation Formats
Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, and Cole, Kathryn E. Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket. United States: N. p., 2016.
Web. doi:10.1016/j.jsb.2016.06.023.
Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, & Cole, Kathryn E. Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket. United States. https://doi.org/10.1016/j.jsb.2016.06.023
Tabackman, Alexa A., Frankson, Rochelle, Marsan, Eric S., Perry, Kay, and Cole, Kathryn E. Wed .
"Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket". United States. https://doi.org/10.1016/j.jsb.2016.06.023. https://www.osti.gov/servlets/purl/1324808.
@article{osti_1324808,
title = {Structure of ‘linkerless’ hydroxamic acid inhibitor-HDAC8 complex confirms the formation of an isoform-specific subpocket},
author = {Tabackman, Alexa A. and Frankson, Rochelle and Marsan, Eric S. and Perry, Kay and Cole, Kathryn E.},
abstractNote = {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.},
doi = {10.1016/j.jsb.2016.06.023},
journal = {Journal of Structural Biology},
number = 3,
volume = 195,
place = {United States},
year = {Wed Jun 29 00:00:00 EDT 2016},
month = {Wed Jun 29 00:00:00 EDT 2016}
}
Web of Science
Works referenced in this record:
PHENIX : building new software for automated crystallographic structure determination
journal, October 2002
- Adams, Paul D.; Grosse-Kunstleve, Ralf W.; Hung, Li-Wei
- Acta Crystallographica Section D Biological Crystallography, Vol. 58, Issue 11
Isoform-specific histone deacetylase inhibitors: The next step?
journal, August 2009
- Balasubramanian, Sriram; Verner, Erik; Buggy, Joseph J.
- Cancer Letters, Vol. 280, Issue 2
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
- Chang, Shurong; McKinsey, Timothy A.; Zhang, Chun Li
- Molecular and Cellular Biology, Vol. 24, Issue 19
Structural Basis of the Antiproliferative Activity of Largazole, a Depsipeptide Inhibitor of the Histone Deacetylases
journal, August 2011
- Cole, Kathryn E.; Dowling, Daniel P.; Boone, Matthew A.
- Journal of the American Chemical Society, Vol. 133, Issue 32
Histone deacetylases (HDACs): characterization of the classical HDAC family
journal, March 2003
- Ruijter, Annemieke J. M. de; Gennip, Albert H. van; Caron, Huib N.
- Biochemical Journal, Vol. 370, Issue 3
Structural Studies of Human Histone Deacetylase 8 and Its Site-Specific Variants Complexed with Substrate and Inhibitors † , ‡
journal, December 2008
- Dowling, Daniel P.; Gantt, Stephanie L.; Gattis, Samuel G.
- Biochemistry, Vol. 47, Issue 51
Structures of Metal-Substituted Human Histone Deacetylase 8 Provide Mechanistic Inferences on Biological Function,
journal, June 2010
- Dowling, Daniel P.; Gattis, Samuel G.; Fierke, Carol A.
- Biochemistry, Vol. 49, Issue 24
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
FDA Approves New Agent for Multiple Myeloma
journal, March 2015
- Fenichel, M. P.
- JNCI Journal of the National Cancer Institute, Vol. 107, Issue 6
Histone deacetylases and cancer
journal, August 2007
- Glozak, M. A.; Seto, E.
- Oncogene, Vol. 26, Issue 37
The many roles of histone deacetylases in development and physiology: implications for disease and therapy
journal, January 2009
- Haberland, Michael; Montgomery, Rusty L.; Olson, Eric N.
- Nature Reviews Genetics, Vol. 10, Issue 1
Structure-Based Design and Synthesis of Novel Inhibitors Targeting HDAC8 from Schistosoma mansoni for the Treatment of Schistosomiasis
journal, March 2016
- Heimburg, Tino; Chakrabarti, Alokta; Lancelot, Julien
- Journal of Medicinal Chemistry, Vol. 59, Issue 6
Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8
journal, March 2015
- Hou, Xuben; Du, Jintong; Liu, Renshuai
- Journal of Chemical Information and Modeling, Vol. 55, Issue 4
Suberoylanilide Hydroxamic Acid as a Potential Therapeutic Agent for Human Breast Cancer Treatment
journal, October 2000
- Huang, Lili; Pardee, Arthur B.
- Molecular Medicine, Vol. 6, Issue 10
Discovery of Inhibitors of Schistosoma mansoni HDAC8 by Combining Homology Modeling, Virtual Screening, and in Vitro Validation
journal, September 2014
- Kannan, Srinivasaraghavan; Melesina, Jelena; Hauser, Alexander-Thomas
- Journal of Chemical Information and Modeling, Vol. 54, Issue 10
Design and evaluation of ‘Linkerless’ hydroxamic acids as selective HDAC8 inhibitors
journal, May 2007
- KrennHrubec, Keris; Marshall, Brett L.; Hedglin, Mark
- Bioorganic & Medicinal Chemistry Letters, Vol. 17, Issue 10
FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma
journal, March 2015
- Lee, Hyon-Zu; Kwitkowski, Virginia E.; Del Valle, Pedro L.
- Clinical Cancer Research, Vol. 21, Issue 12
FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma
journal, October 2007
- Mann, B. S.; Johnson, J. R.; Cohen, M. H.
- The Oncologist, Vol. 12, Issue 10
Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni
journal, September 2013
- Marek, Martin; Kannan, Srinivasaraghavan; Hauser, Alexander-Thomas
- PLoS Pathogens, Vol. 9, Issue 9
Maintenance of cardiac energy metabolism by histone deacetylase 3 in mice
journal, November 2008
- Montgomery, Rusty L.; Potthoff, Matthew J.; Haberland, Michael
- Journal of Clinical Investigation, Vol. 118, Issue 11
Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors
journal, December 2013
- Pottel, Joshua; Therrien, Eric; Gleason, James L.
- Journal of Chemical Information and Modeling, Vol. 54, Issue 1
Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation
journal, February 2015
- Rettig, I.; Koeneke, E.; Trippel, F.
- Cell Death & Disease, Vol. 6, Issue 2
Exploring the Potential binding Sites of Some Known HDAC Inhibitors on Some HDAC8 Conformers by Docking Studies
journal, June 2014
- Sixto-López, Yudibeth; Gómez-Vidal, José A.; Correa-Basurto, José
- Applied Biochemistry and Biotechnology, Vol. 173, Issue 7
Structural Snapshots of Human HDAC8 Provide Insights into the Class I Histone Deacetylases
journal, July 2004
- Somoza, John R.; Skene, Robert J.; Katz, Bradley A.
- Structure, Vol. 12, Issue 7
Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor
journal, October 2004
- Vannini, A.; Volpari, C.; Filocamo, G.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 42
Substrate binding to histone deacetylases as shown by the crystal structure of the HDAC8–substrate complex
journal, August 2007
- Vannini, Alessandro; Volpari, Cinzia; Gallinari, Paola
- EMBO reports, Vol. 8, Issue 9
Works referencing / citing this record:
A Genetically Encoded, Phage‐Displayed Cyclic‐Peptide Library
journal, September 2019
- Wang, Xiaoshan Shayna; Chen, Peng‐Hsun Chase; Hampton, J. Trae
- Angewandte Chemie, Vol. 131, Issue 44
A Genetically Encoded, Phage‐Displayed Cyclic‐Peptide Library
journal, September 2019
- Wang, Xiaoshan Shayna; Chen, Peng‐Hsun Chase; Hampton, J. Trae
- Angewandte Chemie International Edition, Vol. 58, Issue 44
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing
journal, April 2019
- Liu, Jian; Zhu, Yehua; He, Yufang
- Journal of Biomolecular Structure and Dynamics, Vol. 38, Issue 2
Molecular dynamics study of HDAC8-largazole analogues co-crystals for designing potential anticancer compounds
journal, April 2019
- Dewaker, Varun; Srivastava, Pratik Narain; Verma, Saroj
- Journal of Biomolecular Structure and Dynamics, Vol. 38, Issue 4
Examining the stability of binding modes of the co-crystallized inhibitors of human HDAC8 by molecular dynamics simulation
journal, May 2019
- Uba, Abdullahi Ibrahim; Weako, Jackson; Keskin, Özlem
- Journal of Biomolecular Structure and Dynamics
Determination of the binding mechanism of histone deacetylase inhibitors
journal, December 2018
- Meyer-Almes, Franz-Josef
- Chemical Biology & Drug Design, Vol. 93, Issue 6
Structure–activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery
journal, December 2017
- Amin, Sk Abdul; Adhikari, Nilanjan; Jha, Tarun
- Future Medicinal Chemistry, Vol. 9, Issue 18
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing
text, January 2019
- Liu, Jian; Zhu, Yehua; He, Yufang
- Taylor & Francis
Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing
text, January 2019
- Liu, Jian; Zhu, Yehua; He, Yufang
- Taylor & Francis
HDAC8 functions in spindle assembly during mouse oocyte meiosis
journal, February 2017
- Zhang, Kemei; Lu, Yajuan; Jiang, Chaohua
- Oncotarget, Vol. 8, Issue 12
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
- Zhang, Bingbing; Shan, Guangsheng; Zheng, Yinying
- Marine Drugs, Vol. 17, Issue 6