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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Discovery of a novel CD39 inhibitor by DNA-encoded library screening
Simin Wang1, Jiannan Zhao2, Takashi Nakai3
1College of Chemistry, Zhengzhou University, Zhengzhou 450001, China; Pingyuan Laboratory, Zhengzhou 450001, China.
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.
Insights
Researchers discovered a novel CD39 small molecule inhibitor, compound 338, using DNA-encoded library technology. This compound shows promise as an anti-tumor therapeutic agent due to its potent CD39 inhibition and good druggability.
Area of Science:
- Immunology
- Pharmacology
- Biochemistry
Background:
- The ATP-adenosine pathway is crucial for adaptive immunity and influences tumor growth.
- CD39, an extracellular nucleotidase, is a key regulator in this pathway and a potential target for cancer therapy.
Purpose of the Study:
- To discover and characterize novel small molecule inhibitors of CD39 for potential anti-tumor applications.
Main Methods:
- DNA-encoded library (DEL) technology was employed to identify potential CD39 inhibitors.
- Compound 338 was synthesized and its inhibitory activity against CD39 was evaluated.
- Molecular docking and Surface Plasmon Resonance (SPR) were used to assess binding interactions.
- Anti-proliferative effects on tumor cells and toxicity on normal cells were tested.
Main Results:
- A novel CD39 inhibitor, compound 338, was identified with an IC50 value of 68.7 nM.
- Compound 338 demonstrated moderate anti-proliferative effects on tumor cells and low toxicity on normal cell lines.
- Molecular docking and SPR confirmed robust binding interactions between compound 338 and CD39.
Conclusions:
- Compound 338 exhibits strong CD39 inhibitory activity and favorable druggability characteristics.
- This novel inhibitor represents a potential therapeutic agent for anti-tumor therapy and warrants further optimization.
