Molecular Technology for Controlling Epigenetics: Regulation of Histone Acetylation and Methylation by Small Molecules

Histone modifications such as acetylation and methylation control gene transcription independently on DNA base sequence. Such modification system, which is called "epigenetics," plays important roles in regulating cellular functions including cell cycle, immunoresponses, and signal transduction. However, epigenetic aberrations have been found in many abnormal cells and are closely associated with various diseases such as cancer and neurodegenerative disorders. Therefore, molecular technology for controlling epigenetics by small molecules has been of interest both in chemical biology and in epigenetic therapy. To establish this molecular technology, we have studied epigenetic inhibitors focusing on histone modification enzymes, especially on histone deacetylases (HDACs) and histone lysine demethylases (KDMs). These inhibitors have been discovered based on organic chemistry methodology, i.e. C-H activation, click chemistry, targeted drug delivery, and structure-based drug design. Herein we demonstrate the molecular technology for controlling epigenetic mechanism by presenting the design, synthesis, and biological evaluation of HDAC or KDM inhibitors.