論文

査読有り 国際誌
2020年5月6日

Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors.

ChemMedChem
  • Hideaki Niwa
  • ,
  • Shin Sato
  • ,
  • Noriko Handa
  • ,
  • Toru Sengoku
  • ,
  • Takashi Umehara
  • ,
  • Shigeyuki Yokoyama

15
9
開始ページ
787
終了ページ
793
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/cmdc.202000014

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.

リンク情報
DOI
https://doi.org/10.1002/cmdc.202000014
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32166890
ID情報
  • DOI : 10.1002/cmdc.202000014
  • PubMed ID : 32166890

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