Targeting Eph receptors in cancer

描述（由申请人提供）：Eph受体酪氨酸激酶已经成为一个新的重要的癌症靶点家族。包括这个项目的一个小组在内的几个小组的研究表明，在临床前小鼠肿瘤模型中，破坏Eph受体与其配体（ephrin）的结合可以抑制肿瘤的生长。在癌组织中上调的Eph受体也可以用于靶向药物递送肿瘤。尽管Eph受体和ephrin配体之间的结合相互作用是高度混杂的，但该项目实验室之间的合作研究表明，人工配体（如肽和小分子）可以选择性地结合到不同Eph受体的ephrin结合口袋上。因此，可以实现对个别Eph受体的特异性靶向。然而，到目前为止，只有少数抑制ephrin结合的药物被发现。该项目旨在确定具有高亲和力的结构特征，并控制配体与Eph受体结合的选择性和混杂性，以及优化现有的抑制Eph受体-ephrin相互作用的小分子和肽导联。优化后的分子的抗癌作用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射线晶体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具有互补的专业知识，它们之间的密切合作将使每个单独组成部分无法直接达到的成就成为可能。组件1将评估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射线晶体学高分辨率表征Eph受体在高亲和力肽和小分子配体复合物中的界面，并与天然ephrin配体进行比较。组件3将使用NMR表征Eph受体结构域与化合物复合物的结合界面，从而提供结构信息，使其优化。Component 3还将开发肽-药物偶联物，选择性地靶向肿瘤中表达EphA2受体的细胞，这是对使用干扰Eph受体/ephrin生物活性的药物的补充。从所提出的研究中获得的信息有望开发新的方法，利用化合物和肽有效地靶向Eph受体的ephrin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. RELEVANCE (See instructions): We expect that synergistic interactions within the program project will enable the development of new chemical compound- and peptide-based research tools that will be valuable to gain insight into the roles of individual Eph receptors in cancer as well as contribute to the discovery of new strategies to modulate Eph receptor activities to control cancer progression. Our studies proposing to disrupt Eph-ephrin protein interfaces complement drug discovery efforts under development in the pharmaceutical industry to target Eph receptors, which mainly revolve around the more traditional use of antibodies and kinase inhibitors.