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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
PubMed
Summary
This summary is machine-generated.

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.

Keywords:
PharmacologyProtease-activated Receptor 4 (PAR4)ProteasesThrombin

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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.