Overview of the Development of Glutaminase Inhibitors: Achievements and Future Directions
Overview of the Development of Glutaminase Inhibitors: Achievements and Future Directions
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谷氨酰胺酶抑制剂的发展概况：成就与未来方向
DOI：
10.1021/acs.jmedchem.8b00961
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发表时间：
2019-02-14
影响因子：
7.3
通讯作者：
Bian, Jinlei
中科院分区：
文献类型：
--
作者：
Xu, Xi;Meng, Ying;Bian, Jinlei
研究表明，谷氨酰胺代谢已成为一大类恶性肿瘤生长和生存所需的主要能量和物质来源。谷氨酰胺的代谢通常依赖于线粒体谷氨酰胺酶(GLS)的活性，该酶将谷氨酰胺转化为谷氨酸，在生物能量过程中起着重要的作用。因此，最近，GLS已成为小分子治疗干预的关键靶点。目前许多药物化学研究的目标是设计新的有效的GLS抑制剂，然而，到目前为止，只有一种化合物(命名为CB-839)进入了治疗晚期实体瘤和血液系统恶性肿瘤的临床试验。综述了谷氨酰胺代谢抑制剂的发现和开发进展，包括潜在的结合部位、抑制剂鉴定的生化技术、小分子抑制剂的鉴定方法以及谷氨酰胺代谢的未来治疗前景，以期为新型高效谷氨酰胺代谢调节剂的药物开发提供参考和依据。
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.