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

doi:10.1080/14756366.2019.1639694

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 journal › Article › peer-review

16 Citations (Scopus)

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 language	English
Pages (from-to)	1426-1438
Number of pages	13
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	34
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2019.1639694
Publication status	Published - 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.

Keywords

ALK-L1196M mutant
Anaplastic lymphoma kinase
pyrazolopyridine-based inhibitor

ASJC Scopus subject areas

Pharmacology
Drug Discovery

Access to Document

10.1080/14756366.2019.1639694

Cite this

@article{b549fcdb13dd4994900aa68505ec800b,

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

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",

author = "Yunju Nam and Dongkeun Hwang and Namdoo Kim and Seo, {Hong Seog} and Selim, {Khalid B.} and Taebo Sim",

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: {\textcopyright} 2019, {\textcopyright} 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.",

year = "2019",

doi = "10.1080/14756366.2019.1639694",

language = "English",

volume = "34",

pages = "1426--1438",

journal = "Journal of Enzyme Inhibition and Medicinal Chemistry",

issn = "1475-6366",

publisher = "Informa Healthcare",

number = "1",

}

TY - JOUR

T1 - Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

AU - Nam, Yunju

AU - Hwang, Dongkeun

AU - Kim, Namdoo

AU - Seo, Hong Seog

AU - Selim, Khalid B.

AU - Sim, Taebo

N1 - 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.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - ALK-L1196M mutant

KW - Anaplastic lymphoma kinase

KW - pyrazolopyridine-based inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85070969617&partnerID=8YFLogxK

U2 - 10.1080/14756366.2019.1639694

DO - 10.1080/14756366.2019.1639694

M3 - Article

C2 - 31401883

AN - SCOPUS:85070969617

SN - 1475-6366

VL - 34

SP - 1426

EP - 1438

JO - Journal of Enzyme Inhibition and Medicinal Chemistry

JF - Journal of Enzyme Inhibition and Medicinal Chemistry

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this