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
  • 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: [email protected].
  • 5. College of Chemistry, Zhengzhou University, Zhengzhou 450001, China. Electronic address: [email protected].
  • 6. College of Chemistry, Zhengzhou University, Zhengzhou 450001, China; Pingyuan Laboratory, Zhengzhou 450001, China. Electronic address: [email protected].
  • 7. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan 450001, China; Pingyuan Laboratory, Zhengzhou 450001, China. Electronic address: [email protected].
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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