2. Academic Validation
  3. Molecular Basis for the Selective Inhibition of Histone Deacetylase 6 by a Mercaptoacetamide Inhibitor

Molecular Basis for the Selective Inhibition of Histone Deacetylase 6 by a Mercaptoacetamide Inhibitor

  • ACS Med Chem Lett. 2018 Nov 21;9(12):1301-1305. doi: 10.1021/acsmedchemlett.8b00487.
Nicholas J Porter 1,  Sida Shen 2,  Cyril Barinka 3,  Alan P Kozikowski 4,  David W Christianson 1
Affiliations

Affiliations

  • 1 Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
  • 2 Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
  • 3 Laboratory of Structural Biology, Institute of Biotechnology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Czech Republic.
  • 4 StarWise Therapeutics LLC, 505 South Rosa Road, Madison, Wisconsin 53719, United States.
PMID: 30613344 DOI: 10.1021/acsmedchemlett.8b00487
Abstract

Mercaptoacetamide histone deacetylase inhibitors are neuroprotective agents that do not exhibit the genotoxicity associated with more commonly used hydroxamate inhibitors. Here, we present the crystal structure of a selective mercaptoacetamide complexed with the C-terminal catalytic domain of HDAC6. When compared with the structure of a mercaptoacetamide bound to the class I isozyme HDAC8, different interactions are observed with the conserved tandem histidine pair in the active site. These differences likely contribute to the selectivity for inhibition of HDAC6, an important target for Cancer chemotherapy and the treatment of neurodegenerative disease.

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