2. Academic Validation
  3. Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful application of target hopping approach

Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful application of target hopping approach

  • Biochem Pharmacol. 2023 Feb 13;209:115452. doi: 10.1016/j.bcp.2023.115452.
Francesca Romana Ferrari 1,  Carmine Giorgio 1,  Alfonso Zappia 1,  Vigilio Ballabeni 1,  Simona Bertoni 1,  Elisabetta Barocelli 1,  Laura Scalvini 1,  Francesca Galvani 1,  Marco Mor 2,  Alessio Lodola 3,  Massimiliano Tognolini 4
Affiliations

Affiliations

  • 1 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
  • 2 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; Microbiome Research Hub, University of Parma, Parco Area delle Scienze 11/A, I-43124 Parma, Italy.
  • 3 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy. Electronic address: [email protected].
  • 4 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy. Electronic address: [email protected].
PMID: 36792038 DOI: 10.1016/j.bcp.2023.115452
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.

Keywords

Bile acids; FXR; MM-GBSA simulation; Protein–protein interaction; Target hopping.

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