Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors |
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Authors: | Dr. Hideaki Niwa Shin Sato Dr. Noriko Handa Dr. Toru Sengoku Dr. Takashi Umehara Prof. Shigeyuki Yokoyama |
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Affiliation: | 1. RIKEN Systems and Structural Biology Center, Yokohama, 230-0045 Japan;2. RIKEN Systems and Structural Biology Center, Yokohama, 230-0045 Japan RIKEN Center for Life Science Technologies, Yokohama, 230-0045 Japan RIKEN Center for Biosystems Dynamics Research, Yokohama, 230-0045 Japan |
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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. |
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Keywords: | inhibitors protein structures chromatin epigenetics histone demethylase nucleosomes X-ray crystallography |
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