New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Cheombokro, Dong-gu, Daegu 41061, Korea.
Curr Top Med Chem. 2018;18(6):432-443. doi: 10.2174/1568026618666180525100830.
Glutaminase (GLS), which is responsible for the conversion of glutamine to glutamate, plays a vital role in up-regulating cell metabolism for tumor cell growth and is considered to be a valuable therapeutic target for cancer treatment. Based on this important function of glutaminase in cancer, several GLS inhibitors have been developed in both academia and industry. Most importantly, Calithera Biosciences Inc. is actively developing the glutaminase inhibitor CB-839 for the treatment of various cancers, and it is currently being evaluated in phase 1 and 2 clinical trials. In this review, recent efforts to develop small molecule glutaminase inhibitors that target glutamine metabolism in both preclinical and clinical studies are discussed. In particular, more emphasis is placed on CB-839 because it is the only small molecule GLS inhibitor being studied in a clinical setting. The inhibition mechanism is also discussed based on X-ray structure studies of thiadiazole derivatives present in glutaminase inhibitor BPTES. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are described in the hopes of providing useful information for the next generation of GLS inhibitors.
谷氨酰胺酶（GLS）负责将谷氨酰胺转化为谷氨酸，在调节肿瘤细胞生长的细胞代谢中起着至关重要的作用，被认为是癌症治疗的有价值的治疗靶点。基于谷氨酰胺酶在癌症中的这一重要功能，学术界和工业界都开发了几种 GLS 抑制剂。最重要的是，Calithera Biosciences Inc. 正在积极开发谷氨酰胺酶抑制剂 CB-839 用于治疗各种癌症，目前正在进行 1 期和 2 期临床试验。在这篇综述中，讨论了在临床前和临床研究中开发针对谷氨酰胺代谢的小分子谷氨酰胺酶抑制剂的最新进展。特别是，更强调 CB-839，因为它是唯一在临床环境中研究的小分子 GLS 抑制剂。还根据谷氨酰胺酶抑制剂 BPTES 中存在的噻二唑衍生物的 X 射线结构研究讨论了抑制机制。最后，描述了开发新一类 GLS 抑制剂的最新药物化学努力，希望为下一代 GLS 抑制剂提供有用的信息。
