Development and Structural Evaluation of N‐Alkylated trans‐2‐Phenylcyclopropylamine‐Based LSD1 Inhibitors

Abstract Lysine‐specific demethylase 1 (LSD1) is a flavin adenine dinucleotide (FAD)‐dependent enzyme that catalyzes the demethylation of histone H3 and regulates gene expression. Because it is implicated in the regulation of diseases such as acute myeloid leukemia, potent LSD1‐specific inhibitors have been pursued. Trans‐ 2‐phenylcyclopropylamine (2‐PCPA)‐based inhibitors featuring substitutions on the amino group have emerged, with sub‐micromolar affinities toward LSD1 and high selectivities over monoamine oxidases (MAOs). We synthesized two N ‐alkylated 2‐PCPA‐based LSD1 inhibitors, S2116 and S2157, based on the previously developed S2101. S2116 and S2157 exhibited enhanced potency for LSD1 by 2.0‐ to 2.6‐fold, as compared with S2101. In addition, they exhibited improved selectivity over MAOs. Structural analyses of LSD1 co‐crystallized with S2101, S2116, S2157, or another N ‐alkylated inhibitor (FCPA‐MPE) confirmed that the N ‐substituents enhance the potency of a 2‐PCPA‐based inhibitor of LSD1, without constituting the adduct formed with FAD.