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Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.
Nishigaya, Yosuke; Takase, Shohei; Sumiya, Tatsunobu; Sato, Tomohiro; Niwa, Hideaki; Sato, Shin; Nakata, Akiko; Matsuoka, Seiji; Maemoto, Yuki; Hashimoto, Noriaki; Namie, Ryosuke; Honma, Teruki; Umehara, Takashi; Shirouzu, Mikako; Koyama, Hiroo; Yoshida, Minoru; Ito, Akihiro; Shirai, Fumiyuki.
Affiliation
  • Nishigaya Y; Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: yousuke.nishigaya@mb.kyorin-pharm.co.jp.
  • Takase S; School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
  • Sumiya T; Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan.
  • Sato T; Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • Niwa H; Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • Sato S; Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • Nakata A; Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • Matsuoka S; Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • Maemoto Y; School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
  • Hashimoto N; Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan.
  • Namie R; Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan.
  • Honma T; Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • Umehara T; Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • Shirouzu M; Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • Koyama H; Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • Yoshida M; Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Office of University Professor, th
  • Ito A; Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; School of Life Sciences, Tokyo Uni
  • Shirai F; Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: fumiyuki.shirai@riken.jp.
Bioorg Med Chem Lett ; 110: 129856, 2024 Sep 15.
Article in En | MEDLINE | ID: mdl-38914346
ABSTRACT
The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 µM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Histone-Lysine N-Methyltransferase / Epigenesis, Genetic / Enzyme Inhibitors / Anemia, Sickle Cell Limits: Humans Language: En Journal: Bioorg Med Chem Lett / Bioorg. med. chem. lett / Bioorganic & medicinal chemistry letters Journal subject: BIOQUIMICA / QUIMICA Year: 2024 Document type: Article Country of publication: Reino Unido
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Histone-Lysine N-Methyltransferase / Epigenesis, Genetic / Enzyme Inhibitors / Anemia, Sickle Cell Limits: Humans Language: En Journal: Bioorg Med Chem Lett / Bioorg. med. chem. lett / Bioorganic & medicinal chemistry letters Journal subject: BIOQUIMICA / QUIMICA Year: 2024 Document type: Article Country of publication: Reino Unido