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  3. Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment

Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment

  • Bioorg Med Chem Lett. 2024 Jun 22:110:129856. doi: 10.1016/j.bmcl.2024.129856.
Yosuke Nishigaya 1,  Shohei Takase 2,  Tatsunobu Sumiya 3,  Tomohiro Sato 4,  Hideaki Niwa 5,  Shin Sato 5,  Akiko Nakata 6,  Seiji Matsuoka 6,  Yuki Maemoto 2,  Noriaki Hashimoto 3,  Ryosuke Namie 3,  Teruki Honma 4,  Takashi Umehara 5,  Mikako Shirouzu 5,  Hiroo Koyama 7,  Minoru Yoshida 8,  Akihiro Ito 9,  Fumiyuki Shirai 10
Affiliations

Affiliations

  • 1 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.
  • 2 School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
  • 3 Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan.
  • 4 Drug Discovery Computational Chemistry Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • 5 Drug Discovery Structural Biology Platform Unit, RIKEN Center for Biosystems Dynamics Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
  • 6 Drug Discovery Seed Compounds Exploratory Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 7 Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
  • 8 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, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
  • 9 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 University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
  • 10 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.
PMID: 38914346 DOI: 10.1016/j.bmcl.2024.129856
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.

Keywords

G9a inhibitor; Sickle cell disease; Structure-based optimization; Surface plasmon resonance analysis; X-ray crystallography.

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