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
  • 1. Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co. Ltd., 1848 Nogi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: [email protected].
  • 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: [email protected].
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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