文献类型：期刊文献

英文题名：Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors

作者：Zhang, Yanming[1];Ye, Shuang[2];Wang, Yuan[3];Wang, Chuanhao[4];Zhu, Yazhao[4];Wu, Yuelin[4];Zhang, Yongqiang[2];Zhang, Huojun[5];Miao, Zhenyuan[1]

机构：[1]Second Mil Med Univ, Sch Pharm, 325 Guohe Rd, Shanghai 200433, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Frontiers Sci Ctr Optogenet Tech Cell M, Sch Pharm, Shanghai Key Lab New Drug Design, 130 Meilong Rd, Shanghai 200237, Peoples R China;[3]Ningxia Med Univ, Sch Pharm, 1160 Shengli St, Yinchuan 750004, Ningxia, Peoples R China;[4]Shanghai Inst Technol, Sch Chem & Environm Engn, 100 Haiquan Rd, Shanghai 201418, Peoples R China;[5]Second Mil Med Univ, Changhai Hosp, Dept Radiat Oncol, Shanghai 200433, Peoples R China

年份：2022

卷号：59

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001031902800004)】；

基金：This work was supported by grants from the National Natural Science Foundation of China (82173743 and 81872453).

语种：英文

外文关键词：Drug discovery; CD73; Betulinic acid; Immuno-oncology

摘要：The vast research and clinical result have verified the success of cancer immunotherapy. However, there is also facing the enormous challenges such as lack of precise pre-clinical models, optimal combined therapy regimen and acquired resistance to immunotherapy. Adenosine is a potent immune-modulating molecule and overexpression of CD73 on tumor leads to the high concentration of adenosine. Blockade of the key adenosinegenerating enzyme CD73 can be a promising strategy for cancer immunotherapy. Here, we report the discovery of betulinic acid as a novel CD73 inhibitor lead compound by a hit-based substructure search strategy. Subsequent optimization led to the discovery of betulinic acid carbamate derivative ZM514 with 5.2-fold increased potency compared to lead compound. Simultaneously, study has showed that compound ZM514 was not a cytotoxic agent while betulinic acid showed modest antiproliferative activity. The present result provides a valuable inhibitor against the promising immuno-oncology target for further development.