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Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors.
Niwa, Hideaki; Sato, Shin; Handa, Noriko; Sengoku, Toru; Umehara, Takashi; Yokoyama, Shigeyuki.
Afiliación
  • Niwa H; RIKEN Systems and Structural Biology Center, Yokohama, 230-0045, Japan.
  • Sato S; RIKEN Center for Life Science Technologies, Yokohama, 230-0045, Japan.
  • Handa N; RIKEN Center for Biosystems Dynamics Research, Yokohama, 230-0045, Japan.
  • Sengoku T; RIKEN Systems and Structural Biology Center, Yokohama, 230-0045, Japan.
  • Umehara T; RIKEN Center for Life Science Technologies, Yokohama, 230-0045, Japan.
  • Yokoyama S; RIKEN Center for Biosystems Dynamics Research, Yokohama, 230-0045, Japan.
ChemMedChem ; 15(9): 787-793, 2020 05 06.
Article en En | MEDLINE | ID: mdl-32166890
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tranilcipromina / Inhibidores Enzimáticos / Histona Demetilasas / Desarrollo de Medicamentos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tranilcipromina / Inhibidores Enzimáticos / Histona Demetilasas / Desarrollo de Medicamentos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Alemania