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 | |
| Publication status | Published - 2019 Jan 1 |
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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 journal › Article
}
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
PY - 2019/1/1
Y1 - 2019/1/1
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
UR - http://www.scopus.com/inward/citedby.url?scp=85070969617&partnerID=8YFLogxK
U2 - 10.1080/14756366.2019.1639694
DO - 10.1080/14756366.2019.1639694
M3 - Article
VL - 34
SP - 1426
EP - 1438
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
IS - 1
ER -