Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors

The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL ki...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-07, Vol.61 (14), p.6277-6292
Main Authors: Szabadkai, István, Torka, Robert, Garamvölgyi, Rita, Baska, Ferenc, Gyulavári, Pál, Boros, Sándor, Illyés, Eszter, Choidas, Axel, Ullrich, Axel, Őrfi, László
Format: Article
Language:English
Subjects:
Animals
Axl Receptor Tyrosine Kinase
Benzenesulfonamides
Caco-2 Cells
Drug Design
Humans
Mice
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacokinetics
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Structure-Activity Relationship
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Tissue Distribution
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Summary:The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.8b00672