Targeting Eph receptors in cancer

描述(申请人提供)：Eph受体酪氨酸激酶已成为一个新的重要的癌症靶标家族。来自几个小组的研究，包括这个项目的一个小组，已经表明破坏Eph受体与它们的配体-肾上腺素的结合，可以抑制临床前小鼠肿瘤模型中的肿瘤生长。在肿瘤组织中上调的Eph受体也可以用于肿瘤的靶向药物输送。尽管Eph受体和Ephin配体之间的结合作用是高度混杂的，但该项目实验室之间的合作工作表明，多肽和小分子等人工配体可以选择性地与不同Eph受体的ePhin结合口袋结合。因此，可以实现对单个Eph受体的特异性靶向。然而，到目前为止，只有少数几种药物被发现抑制了ePhin的结合。该计划项目旨在确定赋予高亲和力的结构特征，并控制与Eph受体结合的配体的选择性和杂交性，以及优化现有的抑制Eph受体-ephin相互作用的小分子和多肽。优化的分子的抗癌效果将通过培养模型和体内临床前小鼠癌症模型进行评估。三个参与实验室在Eph受体生物学和信号转导、X射线结晶学和生物物理学以及基于核磁共振的药物设计和化学方面拥有互补的专业知识，它们之间的密切合作将使每个单独组成部分无法立即取得的成就。组件1将评估使用通过该计划的联合努力优化的化合物和多肽来调节癌细胞和内皮细胞中的Eph受体功能的策略。组件2将使用X射线结晶学以高分辨率表征高亲和力多肽和小分子配体络合物中Eph受体的界面，并与天然肾上腺素配体进行比较。组件3将使用核磁共振来表征Eph受体结构域与化合物络合物的结合界面，从而提供结构信息，使其能够进行优化。组件3还将开发多肽-药物结合物，以选择性地靶向肿瘤中表达EphA2受体的细胞，这是一种补充使用干扰Eph受体/ePhin生物活性的药物的方法。从拟议的研究中获得的信息有望开发出新的方法，利用化合物和多肽有效地靶向Eph受体的ePhin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.