Novel Approaches for Developing Small Molecules to Target Histone Deacetylases

Epigenetics is the study of heritable phenotypic changes that do not alter the genotype of cells. The role of epigenetic modifications in cancer and inflammation has been investigated frequently. Histone deacetylases (HDACs) are principal modulators of post-translational modifications (PTMs) of histones as well as PTMs of other proteins. The potential of HDACs as drug targets has been demonstrated by the clinical application of several HDAC inhibitors for the treatment of cancer. A remaining challenge is to develop selective inhibitors for the different HDAC isoenzymes and to unravel the functions of these HDAC isoenzymes in specific disease models. In this thesis, novel medicinal chemistry strategies are being applied to develop HDAC antagonists. We also utilize these antagonists to explore the cellular functions of HDAC isoenzymes for better understanding of the implications of HDAC directed epigenetic modulation