Discovery of natural product ellagic acid as a potent CD73 and CD39 dual inhibitor

Yuan Wang; Chuanhao Wang; Yazhao Zhu; Yanming Zhang; Baobao Chen; Yuelin Wu; Jianzhong Yao; Zhenyuan Miao

doi:10.1016/j.bmcl.2020.127758

Discovery of natural product ellagic acid as a potent CD73 and CD39 dual inhibitor

Bioorg Med Chem Lett. 2021 Feb 15:34:127758. doi: 10.1016/j.bmcl.2020.127758. Epub 2020 Dec 24.

Authors

Yuan Wang¹, Chuanhao Wang², Yazhao Zhu², Yanming Zhang³, Baobao Chen², Yuelin Wu⁴, Jianzhong Yao⁵, Zhenyuan Miao⁶

Affiliations

¹ School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, People's Republic of China.
² School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Haiquan Road, Shanghai 201418, People's Republic of China.
³ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, 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. Electronic address: wyldraggon@sit.edu.cn.
⁵ School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, People's Republic of China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: yaojz6601@sina.com.
⁶ School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People's Republic of China. Electronic address: miaozhenyuan@hotmail.com.

PMID: 33359608
DOI: 10.1016/j.bmcl.2020.127758

Abstract

The ATP-adenosine pathway has been recently identified as an attractive immune-oncology target and several drug candidates have been entered clinic trials. Inspired by the report of the first small-molecule CD73inhibitor AB680, we describe the discovery of natural product ellagic acid as a dual CD73 and CD39 inhibitor with an IC₅₀ value of 1.85 ± 0.21 μM and 0.50 ± 0.22 μM, respectively. The result of cytotoxicity assays indicated that ellagic acid is a valuable lead compound with low cytotoxicity effect for immune therapy.

Keywords: CD73 inhibitors; Drug design; Ellagic acid; Immunosuppression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5'-Nucleotidase / antagonists & inhibitors*
5'-Nucleotidase / genetics
5'-Nucleotidase / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apyrase / antagonists & inhibitors*
Apyrase / genetics
Apyrase / metabolism
Biological Products / chemical synthesis
Biological Products / chemistry
Biological Products / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Ellagic Acid / chemical synthesis
Ellagic Acid / chemistry
Ellagic Acid / pharmacology*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
GPI-Linked Proteins / antagonists & inhibitors
GPI-Linked Proteins / genetics
GPI-Linked Proteins / metabolism
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Antineoplastic Agents
Biological Products
Enzyme Inhibitors
GPI-Linked Proteins
Ellagic Acid
5'-Nucleotidase
NT5E protein, human
Apyrase
ENTPD1 protein, human