Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful
Francesca Romana Ferrari1, Carmine Giorgio1, Alfonso Zappia1
1Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
Abstract:
It is well demonstrated the key role of Eph-ephrin system, specifically of EphA2 receptor, in supporting tumor growth, invasion, metastasis and neovascularization. We previously identified FXR agonists as eligible antagonists of Eph-ephrin system. Herein we characterize new commercially available FXR (Farnesoid X Receptor) agonists as potential Eph ligands including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl and Vonafexor. Our exploration based on molecular modelling investigations and binding assays shows that Cilofexor binds specifically and reversibly to EphA2 receptor with a Ki value in the low micromolar range. Furthermore, Cilofexor interferes with the phosphorylation of EphA2 and the cell retraction and rounding in PC3 prostate cancer cells, both events depending on EphA2 activation. In conclusion, we can confirm that target hopping can be a successful approach to discover new moiety of protein-protein inhibitors.
Insights
Researchers identified Cilofexor, a Farnesoid X Receptor (FXR) agonist, as a novel antagonist of the EphA2 receptor, inhibiting cancer cell invasion and metastasis. This discovery highlights target hopping for developing new protein-protein inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The Eph-ephrin system, particularly the EphA2 receptor, is crucial for tumor progression, invasion, metastasis, and neovascularization.
- Previous research identified Farnesoid X Receptor (FXR) agonists as potential antagonists of the Eph-ephrin system.
Purpose of the Study:
- To investigate novel, commercially available FXR agonists as potential EphA2 receptor ligands.
- To characterize the interaction of specific FXR agonists with the EphA2 receptor and their functional consequences in cancer cells.
Main Methods:
- Molecular modeling investigations.
- Binding assays to determine receptor-ligand interactions.
- Functional assays assessing EphA2 phosphorylation and cell morphology changes in PC3 prostate cancer cells.
Main Results:
- Cilofexor was identified as a specific and reversible binder to the EphA2 receptor, with a dissociation constant (Ki) in the low micromolar range.
- Cilofexor demonstrated interference with EphA2 phosphorylation, a key event in EphA2 activation.
- Cilofexor inhibited cell retraction and rounding in PC3 prostate cancer cells, processes dependent on EphA2 signaling.
Conclusions:
- FXR agonists, such as Cilofexor, represent a promising new class of EphA2 receptor antagonists.
- Target hopping, exemplified by this study, is a viable strategy for discovering novel protein-protein interaction inhibitors.
- Cilofexor's ability to inhibit EphA2 activity suggests its potential therapeutic application in cancers where EphA2 signaling is implicated.
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