New framework for the discovery of PRC2 inhibitors: Epigenetic Drugs.

Abstract

Over the past several years, remarkable progress towards the recognition of new therapeutic targets in tumor cells has led to the discovery and development of newer scaffold of anti-tumor drugs. The exploration and exploitation of epigenetic regulation in tumor cells is of immense importance to both the pharmaceutical and academic biomedical literatures. Epigenetic mechanisms are indispensable for normal development and maintenance of tissue-specific gene expression. Disruption of epigenetic processes to eradicate tumor cells is among the most promising intervention for cancer control. Polycomb repressive complex 2 (PRC2), a complex that methylates lysine 27 of histone H3 to promote transcriptional silencing, is involved in orchestrating significant pathways in a cell. Over expression of PRC2 has been found in a number of cancerous malignancies, making a major target for anti-cancer therapy. Despite its well-understood molecular mechanism, hyperactivation and drug resistance mutations in its subunits has become a matter of discussion. This review outlines the current understanding of the components of PRC2 in active complex formation and assesses their potential as a promising therapeutic target for cancer therapy. We also review the effects of mutations in the PRC2 components, in purview of human cancers. Finally, we discuss some of the current challenges for therapeutic drug designs targeting PRC2 complex.