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Protease-Activated Receptor 4 (PAR4)-Tethered Ligand Antagonists Demonstrate Thrombin Liability
Emma M Webb1, Jackson B Cassada1, Heidi E Hamm1,2
1Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-6600, United States.
ACS Pharmacology & Translational Science
|January 15, 2026
Summary
New protease-activated receptor 4 (PAR4) antagonists show promise but also interact with thrombin. Further studies confirmed PAR4 antagonism and identified thrombin as an additional target for these compounds.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Protease-activated receptor 4 (PAR4) plays a role in various physiological processes.
- PAR4 antagonists are being investigated for therapeutic potential.
- Previous research identified PAR4 antagonists from a virtual screen.
Purpose of the Study:
- To characterize the activity and potential off-target effects of newly developed PAR4 antagonists.
- To investigate the interaction of these compounds with thrombin.
Main Methods:
- Ulta-large virtual screening using a PAR4 homology model.
- Fluorescent and chromogenic thrombin activity assays.
- Flow cytometry assays to assess receptor activity.
Main Results:
- The identified compounds effectively antagonize the tethered ligand activation of PAR4.
- Further assays revealed that these PAR4 antagonists also exhibit activity against thrombin.
- Confirmatory assays validated both PAR4 antagonism and thrombin liability.
Conclusions:
- The studied compounds are dual-acting agents, targeting both PAR4 and thrombin.
- The identified thrombin liability necessitates further consideration in the development of these PAR4 antagonists.
- These findings highlight the importance of thorough off-target profiling in drug discovery.
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