Targeting Eph receptors in cancer

描述（由申请人提供）：Eph受体酪氨酸激酶已成为新的重要癌症靶点家族。来自几个小组的研究，包括来自该项目的一个小组，已经表明，破坏Eph受体与其配体肝配蛋白的结合，可以抑制临床前小鼠肿瘤模型中的肿瘤生长。在癌组织中上调的Eph受体也可以用于靶向药物递送至肿瘤。尽管Eph受体和肝配蛋白配体之间的结合相互作用是高度混杂的，但该计划实验室之间的合作工作表明，人工配体如肽和小分子可以选择性地结合不同Eph受体的肝配蛋白结合口袋。因此，可以实现单个Eph受体的特异性靶向。然而，到目前为止，只有少数抑制肝配蛋白结合的药物被鉴定出来。该计划项目旨在定义赋予高亲和力和控制选择性与配体结合Eph受体的混杂性的结构特征，以及优化抑制Eph受体-肝配蛋白相互作用的现有小分子和肽先导物。将使用培养模型和体内临床前小鼠癌症模型评价优化分子的抗癌作用。三个参与实验室在Eph受体生物学和信号转导、X射线晶体学和生物物理学以及基于NMR的药物设计和化学方面具有互补的专业知识，它们之间的密切合作将使每个单独的组分都能取得超越其直接影响的成就。第1部分将评估使用通过该计划的共同努力优化的化合物和肽来调节癌细胞和内皮细胞中Eph受体功能的策略。组分2将使用X射线晶体学以高分辨率表征与高亲和力肽和小分子配体复合的Eph受体与天然肝配蛋白配体相比的界面。组件3将使用NMR来表征与化合物复合的Eph受体结构域的结合界面，从而提供使其优化的结构信息。组分3还将开发肽-药物缀合物以选择性地靶向肿瘤中表达EphA 2受体的细胞，这是与使用干扰Eph受体/肝配蛋白生物活性的试剂互补的方法。从拟议的研究中获得的信息预计将能够开发新的方法，以有效地利用化学化合物和肽靶向Eph受体的肝配蛋白结合口袋。

DESCRIPTION (provided by applicant): The Eph receptor tyrosine kinases have emerged as a new important family of cancer targets. Studies from several groups, including one from this program, have shown that disrupting the binding of Eph receptors with their ligands, the ephrins, inhibits tumor growth in preclinical mouse tumor models. Eph receptors that are upregulated in cancerous tissue can also be exploited for targeted drug delivery to tumors. Although binding interactions between Eph receptors and ephrin ligands are highly promiscuous, collaborative work between laboratories from this program has revealed that artificial ligands such as peptides and small molecules can bind selectively to the ephrin-binding pocket of different Eph receptors. Thus, specific targeting of individual Eph receptors can be achieved. However, only a few agents that inhibit ephrin binding have been identified so far. This program project aims to define the structural features conferring high affinity and controlling selectivity versus promiscuity of ligand binding to the Eph receptors as well as to optimize existing small molecule and peptide leads that inhibit Eph receptor-ephrin interaction. The anticancer effects of the optimized molecules will be evaluated using culture models and in vivo preclinical mouse cancer models. Close collaboration among the three participating laboratories, which have complementary expertise in Eph receptor biology and signal transduction, X-ray crystallography and biophysics, and NMR-based drug design and chemistry, will enable achievements that are beyond the immediate reaches of each individual component. Component 1 will evaluate strategies to modulate Eph receptor function in cancer cells and endothelial cells using chemical compounds and peptides optimized through the combined efforts of the program. Component 2 will use X-ray crystallography to characterize with high resolution the interfaces of Eph receptors in complex with high affinity peptide and small molecule ligands in comparison with the natural ephrin ligands. Component 3 will use NMR to characterize binding interfaces of Eph receptor domains in complex with chemical compounds and thus provide structural information enabling their optimization. Component 3 will also develop peptide-drug conjugates to selectively target cells expressing the EphA2 receptor in tumors, an approach complementary to using agents that interfere with Eph receptor/ephrin biological activities. The information obtained from the proposed studies is expected to enable development of new ways to effectively target the ephrin-binding pocket of Eph receptors using chemical compounds and peptides.