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  3. Thromboxane A2 Synthase Is An Off Target Of The Ces1 Small-molecule Inhibitor Wwl113.
  1. Home
  3. Thromboxane A2 Synthase Is An Off Target Of The Ces1 Small-molecule Inhibitor Wwl113.

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Thromboxane A2 synthase is an off target of the CES1 small-molecule inhibitor WWL113.

Abdolsamad Borazjani1, Kaitlyn Odom1, Adekanye Oluwabori1

  • 1Department of Comparative Biomedical Sciences, Center for Environmental Health Sciences, Mississippi State University, College of Veterinary Medicine, MS 39762, United States.

Prostaglandins & Other Lipid Mediators
|April 5, 2026

View abstract on PubMed

Summary
This summary is machine-generated.

A novel carboxylesterase 1 (CES1) inhibitor, WWL113, unexpectedly targets thromboxane A2 synthase (TBXAS1), reducing inflammatory mediator TxA2 production. WWL113 is recommended over WWL229 for perturbing CES1 activity due to its dual inhibitory action.

Keywords:
Carboxylesterase 1MacrophagesMonocytesSerine hydrolaseTBXAS1WWL113WWL229

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Immunology

Background:

  • Thromboxane A2 (TxA2) is a key inflammatory lipid mediator implicated in cardiovascular disease.
  • Inhibiting thromboxane biosynthesis is a potential strategy to mitigate ischemic events.
  • Carboxylesterase 1 (CES1) is a serine hydrolase involved in lipid metabolism, targeted by small-molecule inhibitors.

Purpose of the Study:

  • To investigate the unexpected inhibitory effect of the CES1 inhibitor WWL113 on thromboxane A2 synthase (TBXAS1).
  • To evaluate the impact of WWL113 on TxA2 production in human monocytic cells.
  • To compare the activity of WWL113 and WWL229 on CES1 and TBXAS1.

Main Methods:

  • Human monocytic THP-1 cells were treated with WWL113 or WWL229, followed by addition of prostaglandin H2 (PGH2).
  • Levels of TxA2 metabolite TxB2 and prostaglandin E2 (PGE2) were quantified using LC-MS/MS.
  • Recombinant human TBXAS1 protein was used to confirm direct inhibition by WWL113.

    • Main Results:

    • WWL113 significantly reduced TxB2 levels in THP-1 cells and lysates, with an IC50 of ~0.1-0.2 µM.
    • WWL113 treatment led to increased PGE2 levels, suggesting a compensatory mechanism.
    • WWL113 demonstrated direct inhibition of recombinant TBXAS1 (IC50 = 226 nM), while WWL229 showed no effect on lipid mediator levels.

    Conclusions:

    • WWL113 possesses dual inhibitory activity against both CES1 and TBXAS1.
    • The anti-inflammatory effects of WWL113 may be partly attributed to its inhibition of TxA2 synthesis.
    • WWL229 is recommended for studies targeting CES1 activity to avoid confounding effects from TBXAS1 inhibition.