Abstract
The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Axl Receptor Tyrosine Kinase
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Humans
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Male
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Mice
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Mice, Inbred ICR
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Molecular Docking Simulation
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Molecular Structure
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Neoplasms / drug therapy*
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Protein Binding
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / therapeutic use*
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Pyrimidinones / chemical synthesis
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Pyrimidinones / metabolism
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Pyrimidinones / therapeutic use*
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Rats
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Pyrimidinones
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Receptor Protein-Tyrosine Kinases
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Axl Receptor Tyrosine Kinase