Structurally Designed trans-2-Phenylcyclopropylamine Derivatives Potently Inhibit Histone Demethylase LSD1/KDM1,,

摘要

Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumornsuppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression bynaltering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1naberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormallynsilenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds toninhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with annantidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibitionnthan tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a kinact/KInvalue of 4560 M-1nsn-1n. In comparison with tranylcypromine, the compound displayed weaker inhibition tonthe monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, werenidentified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability ofnthe inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules arenpotential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-nrelated biological investigations.