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

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1426-1438. doi: 10.1080/14756366.2019.1639694.

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

  • Anaplastic Lymphoma Kinase / antagonists & inhibitors*
  • Anaplastic Lymphoma Kinase / metabolism
  • Apoptosis / drug effects
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Cell Line, Transformed
  • Cell Proliferation / drug effects
  • Chromatography, Liquid
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Docking Simulation
  • Proton Magnetic Resonance Spectroscopy
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Signal Transduction / drug effects
  • Spectrometry, Mass, Electrospray Ionization
  • Structure-Activity Relationship

Substances

  • 1H-pyrazolo(3,4-b)pyridine
  • Enzyme Inhibitors
  • Pyrazoles
  • Pyridines
  • ALK protein, human
  • 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.