Lysine-specific histone demethylase 1A (LSD1) is a flavin-dependent monoamine-oxidase that demethylates mono- and di-methylated lysines, particularly lysine 4 on histone 3 (H3K4). LSD1 is overexpressed in many human cancers, and knock-down studies suggest that loss of LSD1 function inhibits cancer cell growth.<br/><br/>An established mechanism for irreversible inhibition of LSD1 and other MAOs is the reaction of tranylcypromine with the enzyme-bound flavin adenine dinucleotide (FAD). However, tranylcypromine itself shows poor potency and selectivity for LSD1. Herein, we will describe the elaboration of trancylcypromine to a series of N-((1R,2S)-2-phenylcyclopropyl)piperidin-4-amine analogs, resulting in irreversible LSD1 inhibitors with improved potency. MRTX1519 was identified as a lead compound with potency and oral exposure sufficient to cause tumor regressions in xenograft models of cancer.

Discovery of the orally-active irreversible LSD1 inhibitor 1-morpholino-3-(4-(((1R,2S)-2-phenylcyclopropyl)amino)piperidin-1-yl)propan-1-one (MRTX1519) with antitumor activity

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.