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J Med Chem. 2017 Nov 22;60(22):9205-9221. doi: 10.1021/acs.jmedchem.7b01039. Epub 2017 Nov 9.

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

Author information

1
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST) , Daejeon 34141, Korea.
2
Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS) , Daejeon 34141, Korea.
3
Department of Biomedical Sciences, College of Medicine, Inha University , Incheon 22212, Korea.
4
Department of Asan Institute for Life Sciences and Oncology, Asan Medical Center, University of Ulsan, College of Medicine , Seoul 05505, Korea.

Abstract

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 pKa 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 example for systematic investigation of the effect of ionization pH on activity in this system.

PMID:
29091425
DOI:
10.1021/acs.jmedchem.7b01039
[Indexed for MEDLINE]

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