Polyamine-based small molecule epigenetic modulators

Abstract

Chromatin remodelling enzymes such as the histone deacetylases (HDACs) and histone demethylases such as lysine-specific demethylase 1 (LSD1) have been validated as targets for cancer drug discovery. Although a number of HDACinhibitors have been marketed or are in human clinical trials, the search for isoform-specific HDACinhibitors is an ongoing effort. In addition, the discovery and development of compounds targeting histone demethylases are in their early stages. Epigenetic modulators used in combination with traditional antitumor agents such as 5-azacytidine represent an exciting new approach to cancer chemotherapy. We have developed multiple series of HDACinhibitors and LSD1inhibitors that promote the re-expression of aberrantly silenced genes that are important in human cancer. The design, synthesis and biological activity of these analogues is described herein.