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

Lysine-specific demethylase 1 (LSDI/KDMI) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase I (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSDI inhibition restores the expression of abnormally silenced genes in cancerous cells. in this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSDI inhibition than tranylcypromine and the known small LSDI inhibitors in LSD1 demethylation assays, with a k(inact)/K-I value of 4560 M-1 s(-1). In comparison with tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSDI structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSDI residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSDI related biological investigations.