State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China; Department of Otolaryngology Head and Neck Surgery, The Third People's Hospital of Chengdu, Chengdu, 610014, China.
Eur J Med Chem. 2022 Dec 5;243:114686. doi: 10.1016/j.ejmech.2022.114686. Epub 2022 Aug 19.
In this study, we described a series of 2-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)ethan-1-ol analogs as selective GLS1 inhibitors. Systematic exploration of the structure-activity relationship through introducing the hydrophilic skeleton and different chains based on BPTES led to the discovery of the superior derivative compound 24y. Compound 24y showed excellent potency on GLS1 kinase with an IC value of 68 nM, and exhibited more than 220-fold selectivity for GLS2. Moreover, in vitro studies indicated that compound 24y played a function on the mitochondria GLS1 pathway, which was the upregulation of ROS levels. Compound 24y also demonstrated relatively good metabolic stabilities with a bioavailability of 12.4%. Additionally, compound 24y showed antitumor activities in A549 and HCT116 xenograft tumor models, with tumor growth inhibitions of 40.9% and 42.0% by oral gavage of 100 mg/kg, respectively. Taken together, these findings suggest that compound 24y is a potent GLS1 inhibitor, offering a new strategy for the development of novel GLS1 inhibitors.
在这项研究中，我们描述了一系列 2-(1-(1,3,4-噻二唑-2-基)哌啶-4-基)乙醇类似物，它们是选择性 GLS1 抑制剂。通过在 BPTES 的基础上引入亲水骨架和不同链，对构效关系进行了系统的探索，发现了优越的衍生化合物 24y。化合物 24y 对 GLS1 激酶具有优异的效力，IC 值为 68 nM，对 GLS2 的选择性超过 220 倍。此外，体外研究表明，化合物 24y 在线粒体 GLS1 途径中发挥作用，导致 ROS 水平升高。化合物 24y 还表现出相对较好的代谢稳定性，生物利用度为 12.4%。此外，化合物 24y 在 A549 和 HCT116 异种移植肿瘤模型中表现出抗肿瘤活性，口服给予 100 mg/kg 时，肿瘤生长抑制率分别为 40.9%和 42.0%。综上所述，这些发现表明化合物 24y 是一种有效的 GLS1 抑制剂，为开发新型 GLS1 抑制剂提供了一种新策略。
