3,5-Diamino-1,2,4-triazoles as a novel scaffold for potent, reversible LSD1 (KDM1A) inhibitorsElectronic supplementary information (ESI) available: Complete experimental section, including synthetic details and a description of all biological procedures. See DOI: 10.1039/c4md00283k

• Main Authors: Kutz, Craig J, Holshouser, Steven L, Marrow, Ethan A, Woster, Patrick M
• Format: Journal Article
• Language: English
• Published: 19.11.2014
• ISSN: 2040-2503; 2040-2511
• DOI: 10.1039/c4md00283k

The chromatin remodeling amine oxidase lysine-specific demethylase 1 (LSD1) has become an attractive target for the design of specific inhibitors with therapeutic potential. We, and others, have described LSD1 inhibitors that have potential as antitumor agents. Many of the currently known LSD1 inhibitors are poor drug candidates, or are structurally based on the tranylcypromine backbone, thus increasing the potential for off-target effects mediated by other amine oxidases. We now describe a series of potent LSD1 inhibitors based on a novel 1,2,4-triazole scaffold; these inhibitors show a high degree of specificity for LSD1 in vitro , and cause increases in cellular histone 3 dimethyllysine 4 (H3K4me2), a gene transcription activating mark. Importantly, these inhibitors exhibit low toxicity towards mammalian cells in vitro , and thus they may show utility in the treatment of epigenetically-based diseases where cell death is not a desired endpoint. Compounds 6 and 7 represent the first reversible LSD1 inhibitors with minimal cytotoxicity in vitro .