Design, synthesis, structure–activity relationship studies, and evaluation of novel GLS1 inhibitors

Michiko Jo, Keiichi Koizumi*, Mizuho Suzuki, Daisuke Kanayama, Yurie Watanabe, Hiroaki Gouda, Hisashi Mori, Mineyuki Mizuguchi, Takayuki Obita, Yuko Nabeshima, Naoki Toyooka, Takuya Okada*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

3 被引用数 (Scopus)

抄録

Glutaminase converts glutamine into glutamic acid and has two isoforms: glutaminase 1 (GLS1) and glutaminase 2 (GLS2). GLS1 is overexpressed in several tumors, and research to develop glutaminase inhibitors as antitumor drugs is currently underway. The present study examined candidate GLS1 inhibitors using in silico screening and attempted to synthesize novel GLS1 inhibitors and assess their GLS1 inhibitory activities in a mouse kidney extract and against recombinant mouse and human GLS1. Novel compounds were synthesized using compound C as the lead compound, and their GLS1 inhibitory activities were evaluated using the mouse kidney extract. Among the derivatives tested, the trans-4-hydroxycyclohexylamide derivative 2j exhibited the strongest inhibitory activity. We also assessed the GLS1 inhibitory activities of the derivatives 2j, 5i, and 8a against recombinant mouse and human GLS1. The derivatives 5i and 8a significantly decreased the production of glutamic acid at 10 mM. In conclusion, we herein identified two compounds that exhibited GLS1 inhibitory activities with equal potencies as known GLS1 inhibitors. These results will contribute to the development of effective novel GLS1 inhibitors with more potent inhibitory activity.

本文言語英語
論文番号129266
ジャーナルBioorganic and Medicinal Chemistry Letters
87
DOI
出版ステータス出版済み - 2023/05/01

ASJC Scopus 主題領域

  • 生化学
  • 分子医療
  • 分子生物学
  • 薬科学
  • 創薬
  • 臨床生化学
  • 有機化学

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