Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan.
J Med Chem. 2017 Jul 13;60(13):5599-5612. doi: 10.1021/acs.jmedchem.7b00282. Epub 2017 Jun 29.
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.
人类有两个谷氨酰胺酶基因，GLS（GLS1）和 GLS2，每个基因都有两个替代转录本：肾同工型（KGA）和谷氨酰胺酶 C（GAC）用于 GLS，以及肝同工型（LGA）和谷氨酰胺酶 B（GAB）用于 GLS2。从针对 KGA 的 40000 种化合物的高通量筛选中获得了初始命中化合物（Z）-5-((1-(4-溴苯基)-2,5-二甲基-1H-吡咯-3-基)亚甲基)噻唑烷-2,4-二酮（2），是一种噻唑烷-2,4-二酮。随后，合成了一系列噻唑烷-2,4-二酮衍生物。这些化合物中的大多数被发现对 KGA 和 GAC 具有相当的抑制活性，对 GAB 的抑制活性较弱，对 GLS1 比 GLS2 具有中等选择性。研究了化学结构、活性和选择性之间的关系。获得的先导化合物被发现（1）在体外具有抑制细胞生长、集落形成和细胞谷氨酸产生的活性，（2）通过药代动力学研究在血浆中具有高浓度暴露，（3）减少异种移植的人胰腺 AsPC-1 癌细胞在小鼠中的肿瘤大小。
