Identification of 1-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors.

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, . displayed exceptional enzymatic activities (<0.5 nM of IC) against ALK-L1196M as well as against ALK-wt. In addition, is an extremely potent inhibitor of ROS1 (<0.5 nM of IC) and displays excellent selectivity over c-Met. Moreover, strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.