Overexpression of the receptor tyrosine kinase EphA2 is invariably associated with poor prognosis and development of aggressive metastatic cancers. Guided by our recently solved X-ray structure of the complex between an agonistic peptide and EphA2-LBD, we report on a novel agent, targefrin, that binds to EphA2-LBD with a 21 nM dissociation constant by isothermal titration calorimetry and presents an IC₅₀ value of 10.8 nM in a biochemical assay. In cell-based assays, a dimeric version of the agent is as effective as the natural dimeric ligands (ephrinA1-Fc) in inducing cellular receptor internalization and degradation in several pancreatic cancer cell lines. When conjugated with chemotherapy, the agents can effectively deliver paclitaxel to pancreatic cancers in a mouse xenograft study. Given the pivotal role of EphA2 in tumor progression, we are confident that the agents reported could be further developed into innovative EphA2-targeting therapeutics.

中文翻译：

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Targefrin：一种针对 EphA2 配体结合域的有效药物


受体酪氨酸激酶 EphA2 的过度表达总是与不良预后和侵袭性转移性癌症的发展相关。在我们最近解决的激动肽和 EphA2-LBD 之间复合物的 X 射线结构的指导下，我们报告了一种新的药物 Targefrin，它通过等温滴定量热法以 21 nM 解离常数与 EphA2-LBD 结合，并提出了 IC生化测定中₅₀值为 10.8 nM。在基于细胞的检测中，该药物的二聚体版本在诱导多种胰腺癌细胞系中的细胞受体内化和降解方面与天然二聚体配体（ephrinA1-Fc）一样有效。在小鼠异种移植研究中，当与化疗结合时，这些药物可以有效地将紫杉醇递送至胰腺癌。鉴于 EphA2 在肿瘤进展中的关键作用，我们相信所报道的药物可以进一步开发成创新的 EphA2 靶向疗法。