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Cited 12 time in webofscience Cited 13 time in scopus
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Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitorsopen access

Authors
Nam, YunjuHwang, DongkeunKim, NamdooSeo, Hong-SeogSelim, Khalid B.Sim, Taebo
Issue Date
1-Jan-2019
Publisher
TAYLOR & FRANCIS LTD
Keywords
Anaplastic lymphoma kinase; ALK-L1196M mutant; pyrazolopyridine-based inhibitor
Citation
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, v.34, no.1, pp 1426 - 1438
Pages
13
Indexed
SCI
SCIE
SCOPUS
Journal Title
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume
34
Number
1
Start Page
1426
End Page
1438
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/2501
DOI
10.1080/14756366.2019.1639694
ISSN
1475-6366
1475-6374
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.
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Guro Hospital (Department of Cardiology, Guro Hospital)
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