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

ABSTRACT: 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, 10g. 10g displayed exceptional enzymatic activities (<0.5?nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5?nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g 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, 10g 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.

SUBMITTER: Nam Y 

PROVIDER: S-EPMC6713165 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Identification of 1<i>H</i>-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors.

Nam Yunju Y   Hwang Dongkeun D   Kim Namdoo N   Seo Hong-Seog HS   Selim Khalid B KB   Sim Taebo T  

Journal of enzyme inhibition and medicinal chemistry 20191201 1

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, <b>10g</b>. <b>10g</b> displayed exceptional enzymatic activities (<0.5 nM of IC<sub>50</sub>) against ALK-L1196M as well as against ALK-wt. In addition, <b>10g</b> is an extremely potent inhibitor of ROS1 (<0.5 nM of  ...[more]

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