6KGO

LSD1-S2157 five-membered ring adduct model

Summary for 6KGO

• Entry DOI: 10.2210/pdb6kgo/pdb
• Descriptor: Lysine-specific histone demethylase 1A, GLYCEROL, L(+)-TARTARIC ACID, ... (6 entities in total)
• Functional Keywords: demethylase, amine oxidase, chromatin, histone, fad, mechanism-based inhibitor, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 76097.52

Authors

Niwa, H.,Sato, S.,Umehara, T. (deposition date: 2019-07-12, release date: 2020-03-25, Last modification date: 2024-03-27)

Primary citation

Niwa, H.,Sato, S.,Handa, N.,Sengoku, T.,Umehara, T.,Yokoyama, S.
Development and Structural Evaluation of N-Alkylated trans-2-Phenylcyclopropylamine-Based LSD1 Inhibitors.
Chemmedchem, 15:787-793, 2020

PubMed 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.

PubMed: 32166890
DOI: 10.1002/cmdc.202000014

Experimental method

X-RAY DIFFRACTION (2.25 Å)