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

Yunju Nam, Dongkeun Hwang, Namdoo Kim, Hong Seog Seo, Khalid B. Selim, Taebo Sim

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1426-1438
Number of pages13
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Issue number1
Publication statusPublished - 2019

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


  • ALK-L1196M mutant
  • Anaplastic lymphoma kinase
  • pyrazolopyridine-based inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery


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