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Updated: Jul 12, 2026
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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 potential TMPRSS2 inhibitors using integrated computational and experimental screening
Huiru Xie1, Qibo Hu2, Qiuhong Zhang2
1College of Chemistry and Life Science, Beijing University of Technology, Beijing, 100124, China; State Key Laboratory of National Security Specially Needed Medicines, Beijing, 100039, China.
Journal of Molecular Graphics & Modelling
|July 9, 2026
Summary
Researchers identified compound 26 as a promising therapeutic candidate for prostate cancer (PCa). This TMPRSS2 inhibitor demonstrates strong anti-proliferative effects and potential for treating castration-resistant prostate cancer (CRPC).
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Drug Discovery
Background:
- TMPRSS2-ERG fusion gene activates androgen receptor (AR) signaling in prostate cancer (PCa).
- TMPRSS2 protease activity remodels the tumor microenvironment, promoting cancer metastasis.
- Targeting TMPRSS2 offers a therapeutic strategy for castration-resistant prostate cancer (CRPC).
Purpose of the Study:
- To screen and identify novel TMPRSS2-binding lead compounds.
- To evaluate the therapeutic potential of identified compounds against PCa.
Main Methods:
- Integrated virtual screening of compound libraries (ChemDiv, ChemBridge, TargetMol).
- Surface Plasmon Resonance (SPR) assays for binding affinity evaluation.
- In vitro anti-proliferative assays, confocal microscopy, and computational analyses (MD, QM/MM, DCCM).
Main Results:
- 53 hit compounds were identified; six showed higher affinity than Nafamostat.
- Compound 26 exhibited the highest affinity (KD = 3.88 × 10-6 M) and potent anti-proliferative activity (IC50 = 10.95 μM) in LNCaP cells.
- Compound 26 treatment reduced TMPRSS2 staining and mechanistic studies revealed specific ligand-protein interactions.
Conclusions:
- Compound 26 is a promising TMPRSS2-binding lead candidate for prostate cancer therapy.
- The findings provide a foundation for further development and structural optimization of TMPRSS2 inhibitors.
