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

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...

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Published in:Bioorganic & medicinal chemistry letters 2023-09, Vol.93, p.129438-129438, Article 129438
Main Authors: Okada, Takuya, Yamabe, Kaho, Jo, Michiko, Sakajiri, Yuko, Shibata, Tomokazu, Sawada, Ryusuke, Yamanishi, Yoshihiro, Kanayama, Daisuke, Mori, Hisashi, Mizuguchi, Mineyuki, Obita, Takayuki, Nabeshima, Yuko, Koizumi, Keiichi, Toyooka, Naoki
Format: Article
Language:English
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Summary: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 (IC of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2023.129438