Overview of the Development of Glutaminase Inhibitors: Achievements and Future Directions

• Published in: Journal of medicinal chemistry Vol. 62; no. 3; pp. 1096 - 1115
• Main Authors: Xu, Xi, Meng, Ying, Li, Lei, Xu, Pengfei, Wang, Jubo, Li, Zhiyu, Bian, Jinlei
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.02.2019
• Subjects: Animals; Benzophenanthridines - metabolism; Benzophenanthridines - pharmacology; Benzophenanthridines - therapeutic use; Benzoquinones - metabolism; Benzoquinones - pharmacology; Benzoquinones - therapeutic use; Catalytic Domain; Cell Line, Tumor; Drug Discovery; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Glutaminase - antagonists & inhibitors; Glutaminase - chemistry; Glutaminase - metabolism; Humans; Mice; Molecular Docking Simulation; Protein Binding; Sulfides - metabolism; Sulfides - pharmacology; Sulfides - therapeutic use; Thiadiazoles - metabolism; Thiadiazoles - pharmacology; Thiadiazoles - therapeutic use; Thiazolidinediones - metabolism; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.8b00961

It has been demonstrated that glutamine metabolism has become the main energy and building blocks supply for the growth and viability of a potentially large subset of malignant tumors. The glutamine metabolism often depends upon mitochondrial glutaminase (GLS) activity, which converts glutamine to glutamate and serves as a significant role for bioenergetic processes. Thus, recently, the GLS has become a key target for small molecule therapeutic intervention. Numerous medicinal chemistry studies are currently aimed at the design of novel and potent inhibitors for GLS, however, to date, only one compound (named CB-839) have entered clinical trials for the treatment of advanced solid tumors and hematological malignancies. The perspective summarizes the progress in the discovery and development of GLS inhibitors, including the potential binding site, biochemical techniques for inhibitor identification, and approaches for identifying small-molecule inhibitors, as well as future therapeutic perspectives in glutamine metabolism are also put forward in order to provide reference and rational for the drug discovery of novel and potent glutamine metabolism modulators.