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 journalArticle

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.

Original languageEnglish
Pages (from-to)1426-1438
Number of pages13
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume34
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

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Inhibitory Concentration 50
Molecular Targeted Therapy
anaplastic lymphoma kinase
1H-pyrazolo(3,4-b)pyridine
Hydrogen Bonding
Phosphotransferases
Apoptosis
Mutation
crizotinib
3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-amine
pyrazolo(3,4-b)pyridine

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

Cite this

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors. / Nam, Yunju; Hwang, Dongkeun; Kim, Namdoo; Seo, Hong Seog; Selim, Khalid B.; Sim, Taebo.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 34, No. 1, 01.01.2019, p. 1426-1438.

Research output: Contribution to journalArticle

Nam, Yunju ; Hwang, Dongkeun ; Kim, Namdoo ; Seo, Hong Seog ; Selim, Khalid B. ; Sim, Taebo. / Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors. In: Journal of Enzyme Inhibition and Medicinal Chemistry. 2019 ; Vol. 34, No. 1. pp. 1426-1438.
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