Design, synthesis, and structure-activity relationship of novel LSD1 inhibitors based on pyrimidine-thiourea hybrids as potent, orally active antitumor agents.

Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and synthesized a novel series of pyrimidine-thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine-thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.