2. Academic Validation
  3. Application of a fluorine strategy in the lead optimization of betulinic acid to the discovery of potent CD73 inhibitors

Application of a fluorine strategy in the lead optimization of betulinic acid to the discovery of potent CD73 inhibitors

  • Steroids. 2022 Dec:188:109112. doi: 10.1016/j.steroids.2022.109112.
Yanming Zhang 1,  Keli Yang 2,  Shuang Ye 3,  Wenmin Tang 2,  Xuliang Chang 4,  Yuan Wang 4,  Chuanhao Wang 2,  Ying Wang 5,  Yuelin Wu 6,  Zhenyuan Miao 7
Affiliations

Affiliations

  • 1 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, PR China.
  • 2 School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, PR China.
  • 3 School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, PR China.
  • 4 School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, PR China.
  • 5 Department of Dermatology, The First Affiliated Hospital of Second Military Medical University, Shanghai 200433, PR China. Electronic address: wangying88_2@hotmail.com.
  • 6 School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, PR China. Electronic address: wyldraggon@sit.edu.cn.
  • 7 School of Pharmacy, The Second Military Medical University, 325 Guohe Road, Shanghai 200433, PR China. Electronic address: miaozhenyuan@hotmail.com.
PMID: 36150476 DOI: 10.1016/j.steroids.2022.109112
Abstract

The ecto-5'-nucleotidase (CD73) is an important Enzyme in the adenosine pathway and catalyzes the extracellular hydrolysis of adenosine monophosphate (AMP) yielding adenosine which is involved in the inflammation and immunosuppression. Inhibitors of CD73 have potential as novel immunotherapy agents for the treatment of Cancer and Infection. In this study, we discovered a series of fluorinated betulinic acid derivatives as potent CD73 inhibitors by a fluorine scanning strategy. Among these, three compounds ZM522, ZM553 and ZM557 exhibited inhibitory activity with IC50 values of 0.56 uM, 0.74 uM and 0.47 uM, respectively. In addition, these compounds showed a 7-fold, 5-fold and 8-fold increase in activity compared to the positive control drug α, β-methylene adenosine diphosphate (APCP) against the human CD73 Enzyme. Two of these (ZM522 and ZM553) also exhibited effective interferon gamma (INF-γ) elevation and indicated the regulation of rescued T cell activation. Therefore, our study provides both a lead optimization strategy and potential compounds for further development of small molecule CD73 inhibitors.

Keywords

Betulinic acid; CD73 inhibitor; Drug design; Fluorine scanning.

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