1. Design, Synthesis, and Evaluation of Thiazolidine-2,4-dione Derivatives as a Novel Class of Glutaminase Inhibitors.
- Author
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Yeh TK, Kuo CC, Lee YZ, Ke YY, Chu KF, Hsu HY, Chang HY, Liu YW, Song JS, Yang CW, Lin LM, Sun M, Wu SH, Kuo PC, Shih C, Chen CT, Tsou LK, and Lee SJ
- Subjects
- Animals, Antineoplastic Agents blood, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, Drug Design, Enzyme Inhibitors blood, Enzyme Inhibitors therapeutic use, Glutaminase metabolism, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Pancreas drug effects, Pancreas metabolism, Pancreas pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Rats, Rats, Sprague-Dawley, Thiazolidinediones blood, Thiazolidinediones therapeutic use, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glutaminase antagonists & inhibitors, Thiazolidinediones chemistry, Thiazolidinediones pharmacology
- Abstract
Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), 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.
- Published
- 2017
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