- Identification of SNAIL1 Peptide-Based Irreversible Lysine-Specific Demethylase 1-Selective Inactivators
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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.
- Itoh, Yukihiro,Aihara, Keisuke,Mellini, Paolo,Tojo, Toshifumi,Ota, Yosuke,Tsumoto, Hiroki,Solomon, Viswas Raja,Zhan, Peng,Suzuki, Miki,Ogasawara, Daisuke,Shigenaga, Akira,Inokuma, Tsubasa,Nakagawa, Hidehiko,Miyata, Naoki,Mizukami, Tamio,Otaka, Akira,Suzuki, Takayoshi
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p. 1531 - 1544
(2016/03/05)
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- Preparation of Nα-acetyl-Nε-3-(methylpyridinium)lysine (MP-lysine) as a hapten of antibody
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The title compound was prepared from α-tert-butyl Nα-tert-butoxycarbonyl-L-glutamate (Boc-Glu-OBu-t) by N-alkylation of 3-methylpyridine after one carbon-elongation through six steps.
- Matsumoto, Kohsaku,Kumamoto, Takuya,Ishikawa, Tsutomu,Ishii, Erika,Tomitori, Hideyuki,Igarashi, Kazuei
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p. 361 - 367
(2007/10/03)
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