2. Academic Validation
  3. Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity

Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity

  • Bioorg Med Chem Lett. 2023 Sep 1;93:129438. doi: 10.1016/j.bmcl.2023.129438.
Takuya Okada 1,  Kaho Yamabe 2,  Michiko Jo 3,  Yuko Sakajiri 4,  Tomokazu Shibata 5,  Ryusuke Sawada 6,  Yoshihiro Yamanishi 7,  Daisuke Kanayama 8,  Hisashi Mori 9,  Mineyuki Mizuguchi 10,  Takayuki Obita 10,  Yuko Nabeshima 10,  Keiichi Koizumi 11,  Naoki Toyooka 12
Affiliations

Affiliations

  • 1 Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan; Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. Electronic address: tokada@eng.u-toyama.ac.jp.
  • 2 Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan.
  • 3 Division of Presymptomatic Disease, Institute of Natural Medicine, University of Toyama, Toyama 930‑0194, Japan. Electronic address: jo@inm.u-toyama.ac.jp.
  • 4 Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 804-8550, Japan; Graduate School of Informatics, Nagoya University, Chikusa, Nagoya 464-8602, Japan.
  • 5 Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 804-8550, Japan.
  • 6 Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 804-8550, Japan; Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
  • 7 Department of Bioscience and Bioinformatics, Faculty of Computer Science and Systems Engineering, Kyushu Institute of Technology, Fukuoka 804-8550, Japan; Graduate School of Informatics, Nagoya University, Chikusa, Nagoya 464-8602, Japan. Electronic address: yamanishi@i.nagoya-u.ac.jp.
  • 8 Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
  • 9 Department of Molecular Neuroscience, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; Research Center for Pre-Disease Science, University of Toyama, Toyama 930-0194, Japan.
  • 10 Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan.
  • 11 Division of Presymptomatic Disease, Institute of Natural Medicine, University of Toyama, Toyama 930‑0194, Japan; Research Center for Pre-Disease Science, University of Toyama, Toyama 930-0194, Japan.
  • 12 Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan; Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
PMID: 37549852 DOI: 10.1016/j.bmcl.2023.129438
Abstract

GLS1 is an attractive target not only as Anticancer agents but also as candidates for various potential pharmaceutical applications such as Anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.

Keywords

Docking-simulation; GLS1 inhibitor; Glutaminase; Structure–activity relationship; Thiaziazole.

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