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.
Keywords:
ALK-L1196M mutant; Anaplastic lymphoma kinase; pyrazolopyridine-based inhibitor.
MeSH terms
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Anaplastic Lymphoma Kinase / antagonists & inhibitors*
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Anaplastic Lymphoma Kinase / metabolism
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Apoptosis / drug effects
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Carbon-13 Magnetic Resonance Spectroscopy
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Cell Line, Transformed
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Cell Proliferation / drug effects
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Chromatography, Liquid
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Inhibitory Concentration 50
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Molecular Docking Simulation
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Proton Magnetic Resonance Spectroscopy
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyridines / chemistry
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Pyridines / pharmacology*
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Signal Transduction / drug effects
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Spectrometry, Mass, Electrospray Ionization
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Structure-Activity Relationship
Substances
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1H-pyrazolo(3,4-b)pyridine
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Enzyme Inhibitors
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Pyrazoles
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Pyridines
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ALK protein, human
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Anaplastic Lymphoma Kinase
Grants and funding
This study was financially supported by Korea Institute of Science and Technology (KIST), the KU-KIST Graduate School of Converging Science and Technology Program, and Candidate Development Program (NRF-2016M3A9B5940991) of the National Research Foundation of Korea funded by the Ministry of Science and ICT.