title: Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1-Selective Inactivators.
abstract: Inhibition of lysine-specific demethylase 1 (LSD1), a flavin-dependent histone demethylase, has recently emerged as a new strategy for treating cancer and other diseases. LSD1 interacts physically with SNAIL1, a member of the SNAIL/SCRATCH family of transcription factors. This study describes the discovery of SNAIL1 peptide-based inactivators of LSD1. We designed and prepared SNAIL1 peptides bearing a propargyl amine, hydrazine, or phenylcyclopropane moiety. Among them, peptide 3, bearing hydrazine, displayed the most potent LSD1-inhibitory activity in enzyme assays. Kinetic study and mass spectrometric analysis indicated that peptide 3 is a mechanism-based LSD1 inhibitor. Furthermore, peptides 37 and 38, which consist of cell-membrane-permeable oligoarginine conjugated with peptide 3, induced a dose-dependent increase of dimethylated Lys4 of histone H3 in HeLa cells, suggesting that they are likely to exhibit LSD1-inhibitory activity intracellularly. In addition, peptide 37 decreased the viability of HeLa cells. We believe this new approach for targeting LSD1 provides a basis for development of potent selective inhibitors and biological probes for LSD1.
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University , Shomachi, Tokushima 770-8505, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Aihara
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mellini
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tojo
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Research Team for Mechanism of Aging Tokyo Metropolitan Institute of Gerontology , 35-2 Sakae-Cho, Itabashi-ku, Tokyo 173-0015, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsumoto
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University , 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Viswas Raja
authors.initials: VR
authors.lastname: Solomon
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ogasawara
authors.affiliation: Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University , Shomachi, Tokushima 770-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shigenaga
authors.affiliation: Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University , Shomachi, Tokushima 770-8505, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Inokuma
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University , 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Nagoya City University , 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
authors.affiliation: Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology , 1266 Tamura-cho, Nagahama, Shiga 526-0829, Japan.
authors.forename: Tamio
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Institute of Biomedical Sciences and Graduate School of Pharmaceutical Sciences, Tokushima University , Shomachi, Tokushima 770-8505, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto, 606-0823, Japan.|CREST, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000595:Amino Acid Sequence; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D056466:Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human