Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor.
Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor.
复制标题
DOI：
10.1002/cmdc.201200102
复制
发表时间：
2012-06
期刊：
影响因子：
3.4
通讯作者：
Lodola, Alessio
中科院分区：
文献类型：
--
作者：
Tognolini, Massimiliano;Incerti, Matteo;Hassan-Mohamed, Iftiin;Giorgio, Carmine;Russo, Simonetta;Bruni, Renato;Lelli, Barbara;Bracci, Luisa;Noberini, Roberta;Pasquale, Elena B.;Barocelli, Elisabetta;Vicini, Paola;Mor, Marco;Lodola, Alessio
关键词：
Eph-ephrin系统，包括EphA2受体和ephrin-A1配体，在癌变过程中的肿瘤和血管功能中发挥着关键作用。我们之前鉴定出 (3α,5β)-3-羟基胆烷-24-oic 酸（石胆酸）是一种 Eph-ephrin 拮抗剂，能够抑制 EphA2 受体激活，因此有可能用作新型 EphA2 受体靶向剂。在这里，我们基于分子模型研究和置换结合测定，探索了一组重点石胆酸衍生物的结构-活性关系。我们的探索表明，虽然石胆酸的 3-α-羟基在 EphA2 受体的识别中的作用可以忽略不计，但其羧酸盐基团对于破坏 ephrin-A1 与 EphA2 的结合至关重要。我们的研究结果表明，(5β)-cholan-24-oic Acid（胆烷酸）是一种新型化合物，能够竞争性抑制 EphA2-ephrin-A1 相互作用，其效力比石胆酸更高。表面等离振子共振分析表明，胆酸与 EphA2 的配体结合结构域特异性且可逆地结合，稳态解离常数 (KD) 在低微摩尔范围内。此外，胆酸可阻断 EphA2 的磷酸化以及 PC3 前列腺癌细胞中的细胞收缩和变圆，这两种效应取决于肝配蛋白-A1 配体对 EphA2 的激活。这些发现表明，胆酸可以作为模板结构来设计有效的 EphA2 拮抗剂，对阐明该受体在病理条件下所起的作用具有潜在影响。
The Eph–ephrin system, including the EphA2 receptor and the ephrin-A1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist able to inhibit EphA2 receptor activation and therefore potentially useful as a novel EphA2 receptor targeting agent. Here, we explore the structure-activity relationships of a focused set of lithocholic acid derivatives, based on molecular modelling investigation and displacement binding assays. Our exploration shows that while the 3-α-hydroxyl group of lithocholic acid has a negligible role in the recognition of the EphA2 receptor, its carboxylate group is critical for disrupting the binding of ephrin-A1 to the EphA2. As a result of our investigation, we identified (5β)-cholan-24-oic acid (cholanic acid) as a novel compound that competitively inhibits EphA2-ephrin-A1 interaction with higher potency than lithocholic acid. Surface plasmon resonance analysis indicates that cholanic acid binds specifically and reversibly to the ligand-binding domain of EphA2, with a steady-state dissociation constant (KD) in the low micromolar range. Furthermore, cholanic acid blocks the phosphorylation of EphA2 and cell retraction and rounding in PC3 prostate cancer cells, two effects that depend on EphA2 activation by the ephrin-A1 ligand. These findings suggest that cholanic acid can be used as a template structure to design effective EphA2 antagonists, with potential impact in the elucidation of the role played by this receptor in pathological conditions.
登录
查看更多内容
发现有效和可逆的单酰基甘油脂肪酶抑制剂。
影响因子：
--
作者：
King AR;Dotsey EY;Lodola A;Jung KM;Ghomian A;Qiu Y;Fu J;Mor M;Piomelli D
通讯作者：
Piomelli D
影响因子：
2.7
作者：
Barlaam, Bernard;Ducray, Richard;Read, Jon
通讯作者：
Read, Jon
影响因子：
3.6
作者：
Gale, NW;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
影响因子：
2.9
作者：
Kellogg, GE;Fornabaio, M;Abraham, DJ
通讯作者：
Abraham, DJ
影响因子：
5.4
作者：
Durrant JD;McCammon JA
通讯作者：
McCammon JA