Abstract

Structure-based Development of Inhibitors for Epigenetic Targets

Takashi Umehara, Unit Leader, RIKEN Center for Life Science Technologies (CLST)

Post-translational modifications of histones are major sources of epigenetic information for the regulation of eukaryotic gene expression. Epigenetics-regulating compounds are potential drug candidates, since aberrant epigenetic modifications are often linked with cancer- or disease-related cells. We have been performing structural analyses of enzymes and factors that are either substantially or potentially involved in the regulation of epigenetics. The histone demethylase LSD1/KDM1A is a prime example of these drug target proteins, since LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. A comparison of our LSD1 structure, bound with the non-specific inhibitor 2-PCPA, with the monoamine oxidase-B (MAO-B) structure allowed us to develop cell-permeable inhibitors for LSD1 (refs 1-2). I will introduce our structure-based development of the LSD1-specific inhibitors, and studies identifying several roles of the demethylase activity of LSD1 utilizing them as chemical probes. I will also present our biochemical technologies to reconstitute nucleosomes with designed epigenetic information (refs 3-5), which can be applied for a wide variety of epigenetic researches.