Structure-based design of 2,4-diaminopyrimidine derivatives bearing pyrrolyl group as ALK & ROS1 inhibitors

In order to develop potent ALK and ROS1 dual inhibitors, twenty-eight 2,4-diaminopyrimidine derivatives (9a-9n and 10a-10n) bearing pyrrolyl moiety were designed and synthesized based on co-crystal structure of ceritinib with ALKwt protein. Most compounds displayed considerable activity against ALK and ROS1 addicted cells, meanwhile, compound 10d showed excellent activity against Karpas299, H2228 and HCC78 with IC50 values of 0.01, 0.08 and 0.042 μM. Subsequently, seven compounds were selected for kinase studies in vitro, resulting in the discovery of 10d with IC50 values of 1.8, 4.3 and 3.6 nM against ALK, ALKL1196M and ROS1, respectively. Furthermore, the biological assays revealed that compound 10d induced cell apoptosis in a dose-dependent manner. Ultimately, molecular docking studies presented the reasonable and optimal binding interactions with ALKwt and ROS1.