The heterodimeric receptor tyrosine kinase complex formed by HER2 and HER3 can act as an oncogenic driver and is also responsible for rescuing a large number of cancers from a diverse set of targeted therapies. Inhibitors of these proteins, particularly HER2, have dramatically improved patient outcomes in the clinic, but recent studies have demonstrated that stimulating the heterodimeric complex, either via growth factors or by increasing the concentrations of HER2 and HER3 at the membrane, significantly diminishes the activity of the inhibitors. To identify an inhibitor of the active HER2–HER3 oncogenic complex, we developed a panel of Ba/F3 cell lines suitable for ultra-high-throughput screening. Medicinal chemistry on the hit scaffold resulted in a previously uncharacterized inhibitor that acts through preferential inhibition of the active state of HER2 and, as a result, is able to overcome cellular mechanisms of resistance such as growth factors or mutations that stabilize the active form of HER2.

由HER2和HER3形成的异二聚体受体酪氨酸激酶复合物可作为致癌驱动因子，还负责从多种靶向疗法中拯救大量癌症。这些蛋白质的抑制剂，特别是HER2，在临床上可显着改善患者的预后，但是最近的研究表明，通过生长因子或通过增加膜上HER2和HER3的浓度来刺激异二聚体复合物，会大大降低其活性。抑制剂。为了鉴定活性HER2-HER3致癌复合物的抑制剂，我们开发了一组适用于超高通量筛选的Ba / F3细胞系。