Design, Synthesis, and Evaluation of Thiazolidine-2,4-dione Derivatives as a Novel Class of Glutaminase Inhibitors Teng-Kuang Yeh Ching-Chuan Kuo Yue-Zhi Lee Yi-Yu Ke Kuang-Feng Chu Hsing-Yu Hsu Hsin-Yu Chang Yu-Wei Liu Jen-Shin Song Cheng-Wei Yang Li-Mei Lin Manwu Sun Szu-Huei Wu Po-Chu Kuo Chuan Shih Chiung-Tong Chen Lun Kelvin Tsou Shiow-Ju Lee 10.1021/acs.jmedchem.7b00282.s002 https://acs.figshare.com/articles/dataset/Design_Synthesis_and_Evaluation_of_Thiazolidine-2_4-dione_Derivatives_as_a_Novel_Class_of_Glutaminase_Inhibitors/5155777 Humans have two glutaminase genes, <i>GLS</i> (<i>GLS1</i>) and <i>GLS2</i>, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for <i>GLS</i>, and the liver isoform (LGA) and glutaminase B (GAB) for <i>GLS2</i>. Initial hit compound (<i>Z</i>)-5-((1-(4-bromophenyl)-2,5-dimethyl-1<i>H</i>-pyrrol-3-yl)­methylene)­thiazolidine-2,4-dione (<b>2</b>), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice. 2017-06-13 00:00:00 GLS 1 GLS 2 Glutaminase Inhibitors Humans LGA glutaminase GAC GAB 40 000 compounds KGA