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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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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