Drug Design Concepts for LSD1-Selective Inhibitors.

Lysine-specific demethylase 1 (LSD1) is one of the flavin-dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1-selective inhibitors using target-guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1-selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1-selective inhibitors.