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

Abstract

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.

• Authors: István Szabadkai, Robert Torka, Rita Garamvölgyi, Ferenc Baska, Pál Gyulavári, Sándor Boros, Eszter Illyés, Axel Choidas, Axel Ullrich, László Őrfi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 14 Pg. 6277-6292 (Jul 26 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29928803 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Sulfonamides
• Receptor Protein-Tyrosine Kinases
• Axl Receptor Tyrosine Kinase

Topics

• Animals
• Caco-2 Cells
• Drug Design
• Humans
• Mice
• Protein Kinase Inhibitors (chemistry, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors)
• Structure-Activity Relationship
• Sulfonamides (chemistry, pharmacokinetics, pharmacology)
• Tissue Distribution
• Axl Receptor Tyrosine Kinase
• Benzenesulfonamides