Erythropoietin‐producing hepatocellular (EPH) receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion, and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of NVP‐BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application. They only differ by the localization of a single methyl group on either one of two adjacent nitrogen atoms. The two compounds of identical mass revealed different binding modes. Furthermore, both in vitro and in vivo experiments showed that the isomers differ in their kinase affinity and selectivity.

中文翻译：

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NVP-BHG712：区域异构体对EPHrin家族亲和力和选择性的影响

产生促红细胞生成素的肝细胞（EPH）受体是跨膜受体酪氨酸激酶。它们的细胞外结构域特异性结合ephrin A / B配体，并且这种结合调节细胞内激酶的活性。EPH是双向细胞间信号传导，控制细胞形态，粘附和迁移的关键参与者。它们越来越被认为是抗癌药物的靶标。我们分析了NVP-BHG712（NVP）与EPHA2和EPHB4的结合。出乎意料的是，所有测试的市售NVP样品竟然是抑制剂的区域异构体（NVPiso），最初在诺华专利申请中进行了描述。它们的区别仅在于单个甲基在两个相邻氮原子之一上的定位。相同质量的两种化合物显示出不同的结合模式。此外，