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Chem Biol. 2015 Feb 19;22(2):273-84. doi: 10.1016/j.chembiol.2014.12.015.

Identification of histone deacetylase inhibitors with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases.

Author information

1
Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA; Department of Biochemistry and Molecular Biology, College of Life Sciences, Northwest Agriculture and Forestry University, Yangling, Shaanxi 712100, China.
2
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, USA.
3
The Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
4
Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA.
5
Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA; Department of Urology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China.
6
Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA.
7
Reaction Biology Corporation, 1 Great Valley Parkway Suite 2, Malvern, PA 19355, USA.
8
Department of Molecular Therapeutics, Scripps Florida, Jupiter, FL 33458, USA; The Scripps Research Institute Molecular Screening Center, Lead Identification Division, Translational Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
9
Department of Anatomy and Cell Biology, UF Health Cancer Center and UF Genetics Institute, University of Florida College of Medicine, Gainesville, FL 32610, USA. Electronic address: dliao@ufl.edu.

Abstract

Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clinical anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compounds are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compound, UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biological activities in suppressing tumor cell proliferation support further preclinical development of the UF010 class of compounds for potential therapeutic applications.

PMID:
25699604
PMCID:
PMC4365786
DOI:
10.1016/j.chembiol.2014.12.015
[Indexed for MEDLINE]
Free PMC Article

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