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Updated: May 7, 2026
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Target hopping as a useful tool for the identification of novel EphA2 protein-protein antagonists
Massimiliano Tognolini1, Matteo Incerti, Daniele Pala
1Dipartimento di Farmacia, Università degli Studi di Parma, V. le delle Scienze 27 A, 43124 Parma (Italy).
Abstract:
Lithocholic acid (LCA), a physiological ligand for the nuclear receptor FXR and the G-protein-coupled receptor TGR5, has been recently described as an antagonist of the EphA2 receptor, a key member of the ephrin signalling system involved in tumour growth. Given the ability of LCA to recognize FXR, TGR5, and EphA2 receptors, we hypothesized that the structural requirements for a small molecule to bind each of these receptors might be similar. We therefore selected a set of commercially available FXR or TGR5 ligands and tested them for their ability to inhibit EphA2 by targeting the EphA2-ephrin-A1 interface. Among the selected compounds, the stilbene carboxylic acid GW4064 was identified as an effective antagonist of EphA2, being able to block EphA2 activation in prostate carcinoma cells, in the micromolar range. This finding proposes the "target hopping" approach as a new effective strategy to discover new protein-protein interaction inhibitors.
Insights
Researchers discovered that GW4064, a drug targeting FXR and TGR5 receptors, can also inhibit EphA2 receptor activity. This finding offers a novel "target hopping" strategy for developing new protein-protein interaction inhibitors for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Lithocholic acid (LCA) interacts with FXR, TGR5, and EphA2 receptors.
- EphA2 receptor is implicated in tumor growth via the ephrin signaling system.
Purpose of the Study:
- To investigate if structural similarities exist for small molecules binding FXR, TGR5, and EphA2.
- To identify FXR or TGR5 ligands that inhibit EphA2 receptor activity.
Main Methods:
- Screening of commercially available FXR/TGR5 ligands for EphA2 inhibition.
- Testing compounds against the EphA2-ephrin-A1 interface.
- Evaluating EphA2 activation blockade in prostate carcinoma cells.
Main Results:
- GW4064, a stilbene carboxylic acid, demonstrated effective EphA2 antagonism.
- EphA2 activation was inhibited by GW4064 in prostate cancer cells at micromolar concentrations.
Conclusions:
- The study validates the
- target hopping
- approach for discovering novel protein-protein interaction inhibitors.
- GW4064 represents a potential lead compound for targeting EphA2 in cancer therapy.
