Identification of 4-Phenoxyquinoline Based Inhibitors for L1196M Mutant of Anaplastic Lymphoma Kinase by Structure-Based Design

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Dysregulation of anaplastic lymphoma kinase (ALK) has been detected in nonsmall cell lung cancer (NSCLC) in the form of EML4-ALK fusion. Secondary mutations opposing activity of the first generation ALK inhibitor crizotinib came into existence, requiring mutation-targeting drug discovery for the powerful second-line treatment. In this study, we report 4-phenoxyquinoline-based inhibitors that overcome crizotinib resistance to ALK L1196M, discovered by the fragment-growing strategy. The protonation of 4-aminoquinoline core could interrupt the ability the N atom of quinoline to act as a hydrogen bond acceptor; therefore, the pK(a) and calculated ionization pH values of relevant pyridine-based core moieties were carefully analyzed. The replacement of amine linkage with ether resulted in single-digit nanomolar range inhibitors. The inhibitors exhibited significant antiproliferative effects on H2228 CR crizotinib-resistant cells by decreasing PI3K/AKT and MAPK signaling. This work constitutes the first of ionization pH on activity in this system.
Publisher
AMER CHEMICAL SOC
Issue Date
2017-11
Language
English
Article Type
Article
Keywords

CELL LUNG-CANCER; RECEPTOR TYROSINE KINASE; EML4-ALK FUSION GENE; CRIZOTINIB RESISTANCE; ALK INHIBITORS; DISCOVERY; MUTATION; CERITINIB; ALECTINIB; OVERCOME

Citation

JOURNAL OF MEDICINAL CHEMISTRY, v.60, no.22, pp.9205 - 9221

ISSN
0022-2623
DOI
10.1021/acs.jmedchem.7b01039
URI
http://hdl.handle.net/10203/228596
Appears in Collection
CH-Journal Papers(저널논문)
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