Drug Discovery and Development

HDAC Inhibitor Drug Discovery

Design of Histone Deacetylase Inhibitors as Potential anti-cancer agents

Histone Deacetylase (HDAC) inhibitors represent a budding class of targeted anti-cancer agents. This structurally diverse group of molecules can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. Structural and chemical data have been used in the design of novel HDAC inhibitors with more preferred properties. For the two classes of HDAC, only a few are emerging as preferential inhibitors and even fewer are able to discriminate efficiently among HDACs that belong to the same class. This limitation has diminutive relevance to the use of HDAC inhibitors as potential anti-tumor drugs. Of the different classes of HDAC the class I and Class II are considered the main targets for cancer. HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of molecular alterations present in different cancer cells. Thus, we are indeed interested in understanding the plurality of mechanism of HDACi in different pathways/processes and design a novel Pan-HDACi as an effective anti-cancer agent.

Publications:

Kalyanamoorthy Subha and Gopal Ramesh Kumar (2008) Assessment for the identification of better HDAC inhibitor class through binding energy calculations and descriptor analysis.Bioinformation.3(5), 218-222. Pubmed