Development and Structural Evaluation of N-alkylated phenylcyclopropylamine-based LSD1 Inhibitors.

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 submicromolar 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.

Exogenous application of histone demethylase inhibitor mimics FLD loss-of-function phenotype in terms of systemic acquired resistance in Arabidopsis thaliana.

Plants often learn from previous infections to mount higher level of resistance during subsequent infections, a phenomenon referred to as systemic acquired resistance (SAR). During primary infection, mobile signals generated at the infection site subsequently move to the rest of plant to activate SAR. SAR activation is associated with alteration in the nucleosomal composition at the promoters of several defense-related genes.
However, genetic regulations of such epigenetic modifications are largely obscure. Recently, we have demonstrated that Reduced Systemic immunity1/FLOWERING LOCUS D (RSI1; alias FLD) a homolog of human histone demethylase, is required for SAR development in Arabidopsis.
Here, we report that exogenous application of a histone demethylase inhibitor trans-2-phenylcyclopropylamine (2-PCPA) mimics rsi1/fld loss-of-function phenotypes in terms of SAR and associated histone demethylation at the promoters of PR1, WRKY 29, and WRKY6 genes, and as well as flowering phenotypes. Our results suggest histone demethylase activity of FLD is important for controlling SAR activation.

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