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 IC₅₀ 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-thiadiazol-2-yl)piperidin-4-yl)ethan-1-ol 类似物作为选择性 GLS1 抑制剂。通过引入基于BPTES的亲水骨架和不同链系统探索构效关系，发现了优越的衍生化合物24y。化合物24y对 GLS1 激酶表现出优异的效力，IC ₅₀值为 68 nM，对 GLS2 的选择性高出 220 倍以上。此外，体外研究表明，化合物24y在线粒体 GLS1 通路上发挥作用，即上调 ROS 水平。复合24y还表现出相对良好的代谢稳定性，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显示出抗肿瘤活性，口服管饲 100 mg/kg 的肿瘤生长抑制率分别为 40.9% 和 42.0%。总之，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 抑制剂提供了新策略。