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

Takuya Okada; Kaho Yamabe; Michiko Jo; Yuko Sakajiri; Tomokazu Shibata; Ryusuke Sawada; Yoshihiro Yamanishi; Daisuke Kanayama; Hisashi Mori; Mineyuki Mizuguchi; Takayuki Obita; Yuko Nabeshima; Keiichi Koizumi; Naoki Toyooka

doi:10.1016/j.bmcl.2023.129438

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. Epub 2023 Aug 6.

Authors

Takuya Okada¹, Kaho Yamabe², Michiko Jo³, Yuko Sakajiri⁴, Tomokazu Shibata⁵, Ryusuke Sawada⁶, Yoshihiro Yamanishi⁷, Daisuke Kanayama⁸, Hisashi Mori⁹, Mineyuki Mizuguchi¹⁰, Takayuki Obita¹⁰, Yuko Nabeshima¹⁰, Keiichi Koizumi¹¹, Naoki Toyooka¹²

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.

MeSH terms

Antineoplastic Agents* / pharmacology
Glutaminase / antagonists & inhibitors
Thiadiazoles* / chemistry
Thiadiazoles* / pharmacology

Substances

Antineoplastic Agents
Glutaminase
Thiadiazoles
GLS protein, human