2. Academic Validation
  3. Discovery of a novel CD39 inhibitor by DNA-encoded library screening

Discovery of a novel CD39 inhibitor by DNA-encoded library screening

  • Bioorg Med Chem Lett. 2025 Jun 2:127:130294. doi: 10.1016/j.bmcl.2025.130294.
Simin Wang 1,  Jiannan Zhao 2,  Takashi Nakai 3,  Suyi Chen 2,  Yongtao Duan 4,  Ruijun Li 5,  Chuanjun Song 6,  Yongfang Yao 7
Affiliations

Affiliations

  • 1 College of Chemistry, Zhengzhou University, Zhengzhou 450001, China; Pingyuan Laboratory, Zhengzhou 450001, China.
  • 2 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 WuXi AppTec, Natick, MA 01760, USA.
  • 4 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. Electronic address: duanyongtao860409@163.com.
  • 5 College of Chemistry, Zhengzhou University, Zhengzhou 450001, China. Electronic address: liruijun@zzu.edu.cn.
  • 6 College of Chemistry, Zhengzhou University, Zhengzhou 450001, China; Pingyuan Laboratory, Zhengzhou 450001, China. Electronic address: chjsong@zzu.edu.cn.
  • 7 School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China; Pingyuan Laboratory, Zhengzhou 450001, China. Electronic address: yongfangyao@zzu.edu.cn.
PMID: 40466956 DOI: 10.1016/j.bmcl.2025.130294
Abstract

The ATP-adenosine pathway, as a key regulator of adaptive immunity, can regulate tumor growth and proliferation, which is an important direction of anti-tumor immunity research. As a rate-limiting extracellular nucleotidase in eATP hydrolysis, CD39 is a promising target for Anticancer therapy. In this study, we discovered a novel CD39 small molecule inhibitor (compound 338) by DNA-encoded library (DEL) technology. Subsequently, compound 338 was synthesized and tested with promising inhibitory effect which IC50 value was 68.7 nM against CD39. It also showed moderate anti-proliferative effects on tumor cells and low toxicity on normal cell lines. Meanwhile, molecular docking and SPR results demonstrated that 338 had a robust binding interaction with CD39. The druggability of 338 was predicted. In conclusion, the novel compound 338 showed strong CD39 inhibitory activity and good druggability, which can be used as a potential anti-tumor therapeutic agent and can be optimized in further studies.

Keywords

Anti-tumor; CD39; DNA-encoded library.

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