Design, synthesis, and pharmacological evaluation of 2-(1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl)ethan-1-ol analogs as novel glutaminase 1 inhibitors.

ABSTRACT

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.