第二代FXR激动剂作为有效EphA2拮抗剂的药理学特征：目标跳跃方法的成功应用。
Pharmacological characterization of second generation FXR agonists as effective EphA2 antagonists: A successful application of target hopping approach.
发表日期：2023 Feb 13
作者：
Francesca Romana Ferrari, Carmine Giorgio, Alfonso Zappia, Vigilio Ballabeni, Simona Bertoni, Elisabetta Barocelli, Laura Scalvini, Francesca Galvani, Marco Mor, Alessio Lodola, Massimiliano Tognolini
来源：
BIOCHEMICAL PHARMACOLOGY
摘要：
Eph-ephrin系统，特别是EphA2受体，在支持肿瘤生长、侵袭、转移和新生血管形成中扮演着关键角色已被充分证明。我们之前已经确认FXR激动剂是Eph-ephrin系统的合适拮抗剂。在此，我们对新的商业可用FXR（Farnesoid X受体）激动剂进行了特征化，作为潜在的Eph配体，包括Cilofexor、Nidufexor、Tropifexor、Turofexorate异丙酯和Vonafexor。基于分子建模研究和结合实验的探索表明，Cilofexor以低微摩尔范围的Ki值与EphA2受体特异性、可逆性地结合。此外，Cilofexor干扰了EphA2的磷酸化以及PC3前列腺癌细胞的细胞缩回和圆形化，这两个事件都依赖于EphA2激活。总之，我们可以确认目标跳跃可以是发现蛋白质-蛋白质抑制剂新成分的成功方法。版权所有©2023 Elsevier Inc.。保留所有权利。
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.Copyright © 2023 Elsevier Inc. All rights reserved.