The long-term goal of this project is to distinguish between the individual functions of the eleven known human histone deacetylase (HDAC) proteins. HDAC proteins are transcription factors that repress transcription by deacetylating nucleosomal histones. Studies using small molecule inhibitors of HDAC proteins have demonstrated their importance in cell cycle regulation, tissue differentiation, and cancer formation. In fact, small molecule inhibitors of HDAC proteins are being developed to treat certain diseases, including myeloid leukemia. The nonspecific inhibition of all eleven known human HDAC proteins by small molecule inhibitors, however, complicates the determination of which HDAC plays a causative role in disease development. Rigorous characterization of the biological relevance of each of the known HDAC proteins would aid in development of pharmaceutical agents to treat disease. The short-term goal of this proposal is to focus on characterizing the individual functions of HDAC1. A bioorganic approach will be taken where the small molecule HDAC inhibitor trichostatin will be used to deduce the individual functions of HDAC1. Specifically, mutant protein of HDAC1 that has altered sensitivity to small molecule inhibition will be used to document their individual effects on gene expression. The experiments in this proposal aim to characterize the specific activities of HDAC1 as a first step toward identifying the individual functions of all human HDAC proteins. The proposed project will lay the foundation for the ultimate development of pharmaceutical agents targeting HDAC proteins.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Carter, Anthony D
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Wayne State University
Schools of Arts and Sciences
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Padige, Geetha; Negmeldin, Ahmed T; Pflum, Mary Kay H (2015) Development of an ELISA-Based HDAC Activity Assay for Characterization of Isoform-Selective Inhibitors. J Biomol Screen 20:1277-85
Garre, Satish; Senevirathne, Chamara; Pflum, Mary Kay H (2014) A comparative study of ATP analogs for phosphorylation-dependent kinase-substrate crosslinking. Bioorg Med Chem 22:1620-5
Senevirathne, Chamara; Pflum, Mary Kay H (2013) Biotinylated phosphoproteins from kinase-catalyzed biotinylation are stable to phosphatases: implications for phosphoproteomics. Chembiochem 14:381-7
Choi, Sun Ea; Pflum, Mary Kay H (2012) The structural requirements of histone deacetylase inhibitors: suberoylanilide hydroxamic acid analogs modified at the C6 position. Bioorg Med Chem Lett 22:7084-6
Choi, Sun Ea; Weerasinghe, Sujith V W; Pflum, Mary Kay H (2011) The structural requirements of histone deacetylase inhibitors: Suberoylanilide hydroxamic acid analogs modified at the C3 position display isoform selectivity. Bioorg Med Chem Lett 21:6139-42
Weerasinghe, Sujith V W; Wambua, Magdalene; Pflum, Mary Kay H (2010) A histone deacetylase-dependent screen in yeast. Bioorg Med Chem 18:7586-92
Weerasinghe, Sujith V W; Estiu, Guillermina; Wiest, Olaf et al. (2008) Residues in the 11 A channel of histone deacetylase 1 promote catalytic activity: implications for designing isoform-selective histone deacetylase inhibitors. J Med Chem 51:5542-51
Bieliauskas, Anton V; Pflum, Mary Kay H (2008) Isoform-selective histone deacetylase inhibitors. Chem Soc Rev 37:1402-13
Singh, Erinprit K; Ravula, Suchitra; Pan, Chung-Mao et al. (2008) Synthesis and biological evaluation of histone deacetylase inhibitors that are based on FR235222: a cyclic tetrapeptide scaffold. Bioorg Med Chem Lett 18:2549-54
Bieliauskas, Anton V; Weerasinghe, Sujith V W; Pflum, Mary Kay H (2007) Structural requirements of HDAC inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acid. Bioorg Med Chem Lett 17:2216-9

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