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

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 antago-nists 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 Vona-fexor. 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.

Automated summary

It has been demonstrated that the Eph-ephrin system, particularly the EphA2 receptor, plays a key role in supporting tumor growth, invasion, metastasis, and neovascularization. In this study, new commercially available FXR agonists, including Cilofexor, Nidufexor, Tropifexor, Turofexorate isopropyl, and Vonafexor, were characterized as potential Eph ligands. Molecular modeling investigations and binding assays showed that Cilofexor specifically and reversibly binds to the EphA2 receptor with a ki value in the low micromolar range.