Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics

作者：Chen, Yangyang; Tan, Lun; Gao, Jing; Lin, Congcong; Wu, Fengbo^*; Li, Yang^*; Zhang, Jifa^*

来源：European Journal of Medicinal Chemistry, 2023, 252: 115306.

DOI：10.1016/j.ejmech.2023.115306

• Glutaminase-1
• Small -molecule inhibitors
• Structure -activity relationships (SARs)
• X-ray co -crystal structure analyses

Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

• 单位
  哈尔滨医科大学; 四川大学; y