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Molecules 2018, 23(5), 1099; https://doi.org/10.3390/molecules23051099

Design, Synthesis, and In Vitro Evaluation of Novel Histone H3 Peptide-Based LSD1 Inactivators Incorporating α,α-Disubstituted Amino Acids with γ-Turn-Inducing Structures

1
Department of Chemistry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan
2
Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo 169-8555, Japan
3
Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
*
Authors to whom correspondence should be addressed.
Academic Editor: Takaomi Sanda
Received: 2 May 2018 / Revised: 4 May 2018 / Accepted: 4 May 2018 / Published: 6 May 2018
(This article belongs to the Special Issue Transcription Factors as Therapeutic Targets)
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Abstract

Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1. Based on this, we designed and synthesized novel histone H3 peptide-based LSD1 inactivators 2ac by incorporating various α,α-disubstituted amino acids with γ-turn-inducing structures. Among synthetic peptides 2ac, peptide 2b incorporating two 1-aminocyclohexanecarboxylic acids at both sides of a lysine residue bearing a trans-2-phenylcyclopropylamine (PCPA) moiety, which is a pharmacophore for LSD1 inactivation, was the most potent and selective LSD1 inactivator. These findings are useful for the further development of histone H3 peptide-based LSD1 inactivators. View Full-Text
Keywords: epigenetics; histone; lysine-specific demethylase 1 (LSD1); inhibitor; γ-turn structure epigenetics; histone; lysine-specific demethylase 1 (LSD1); inhibitor; γ-turn structure
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Ota, Y.; Kakizawa, T.; Itoh, Y.; Suzuki, T. Design, Synthesis, and In Vitro Evaluation of Novel Histone H3 Peptide-Based LSD1 Inactivators Incorporating α,α-Disubstituted Amino Acids with γ-Turn-Inducing Structures. Molecules 2018, 23, 1099.

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