Lysine-Specific Demethylase 1-Selective Inactivators: Protein-Targeted Drug Delivery Mechanism†
Daisuke Ogasawara
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Search for more papers by this authorDr. Yukihiro Itoh
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorDr. Hiroki Tsumoto
World-Leading Drug Discovery Research Center, Kyoto University, Kyoto 606-8501 (Japan)
Search for more papers by this authorDr. Taeko Kakizawa
Organic Chemistry National Institute of Health Sciences, Tokyo 158-8501 (Japan)
Search for more papers by this authorDr. Koshiki Mino
Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Search for more papers by this authorDr. Kiyoshi Fukuhara
Organic Chemistry National Institute of Health Sciences, Tokyo 158-8501 (Japan)
Search for more papers by this authorProf. Hidehiko Nakagawa
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Search for more papers by this authorDr. Makoto Hasegawa
Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Tamio Mizukami
Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Tamio Mizukami, Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Naoki Miyata, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Takayoshi Suzuki, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Naoki Miyata
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Tamio Mizukami, Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Naoki Miyata, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Takayoshi Suzuki, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Takayoshi Suzuki
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
PRESTO (Japan) Science and Technology Agency (JST), Saitama 332-0012 (Japan)
Tamio Mizukami, Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Naoki Miyata, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Takayoshi Suzuki, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorDaisuke Ogasawara
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Search for more papers by this authorDr. Yukihiro Itoh
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorDr. Hiroki Tsumoto
World-Leading Drug Discovery Research Center, Kyoto University, Kyoto 606-8501 (Japan)
Search for more papers by this authorDr. Taeko Kakizawa
Organic Chemistry National Institute of Health Sciences, Tokyo 158-8501 (Japan)
Search for more papers by this authorDr. Koshiki Mino
Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Search for more papers by this authorDr. Kiyoshi Fukuhara
Organic Chemistry National Institute of Health Sciences, Tokyo 158-8501 (Japan)
Search for more papers by this authorProf. Hidehiko Nakagawa
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Search for more papers by this authorDr. Makoto Hasegawa
Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Tamio Mizukami
Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Tamio Mizukami, Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Naoki Miyata, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Takayoshi Suzuki, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Naoki Miyata
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Tamio Mizukami, Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Naoki Miyata, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Takayoshi Suzuki, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorCorresponding Author
Prof. Takayoshi Suzuki
Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
PRESTO (Japan) Science and Technology Agency (JST), Saitama 332-0012 (Japan)
Tamio Mizukami, Graduate School of Bio-Science, Nagahama Institute of Bio-Science Technology, 1226 Tamura-cho, Nagahama, Shiga 526-0829 (Japan)
Naoki Miyata, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, Aichi 467-8603 (Japan)
Takayoshi Suzuki, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 13 Nishitakatsukasa-cho, Taishogun Kita-ku, Kyoto 603-8334 (Japan)
Search for more papers by this authorWe thank Mie Tsuchida, Dr. Yasunao Hattori, and Prof. Kenichi Akaji for their technical support. This work was supported in part by JST PRESTO program (T.S.), a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (T.S. and Y.I.), Ho-ansha Foundation (T.S), Takeda Science Foundation (T.S.), Naito Foundation (T.S.), and NOVARTIS Foundation (Japan) for the promotion of science (T.S.).
Graphical Abstract
Drug drop off: Given that lysine-specific demethylase 1 (LSD1) could be potently and selectively inactivated by delivering phenylcyclopropylamine (PCPA), a weak and nonselective LSD1 inhibitor, directly to the enzyme's active site, a novel series of LSD1 inactivators (1) were designed. Biological and mechanistic studies indicate that 1 inhibits LSD1 potently and selectively.
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