2. Academic Validation
  3. Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors

Discovery and optimization of betulinic acid derivatives as novel potent CD73 inhibitors

  • Bioorg Med Chem. 2022 Apr 1;59:116672. doi: 10.1016/j.bmc.2022.116672.
Yanming Zhang 1,  Shuang Ye 2,  Yuan Wang 3,  Chuanhao Wang 4,  Yazhao Zhu 4,  Yuelin Wu 4,  Yongqiang Zhang 5,  Huojun Zhang 6,  Zhenyuan Miao 7
Affiliations

Affiliations

  • 1 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China.
  • 2 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China.
  • 3 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, People's Republic of China.
  • 4 School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, People's Republic of China.
  • 5 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China. Electronic address: [email protected].
  • 6 Department of Radiation Oncology, Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: [email protected].
  • 7 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: [email protected].
PMID: 35217359 DOI: 10.1016/j.bmc.2022.116672
Abstract

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 adenosine-generating 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.

Keywords

Betulinic acid; CD73; Drug discovery; Immuno-oncology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-146759
    CD73 Inhibitor