Avapritinib: A Selective Inhibitor of KIT and PDGFRα that Reverses ABCB1 and ABCG2-Mediated Multidrug Resistance in Cancer Cell Lines
| Autor: | Yang-Hui Huang, Sung-Han Hsiao, Suresh V. Ambudkar, Jyun-Cheng Wang, Tai-Ho Hung, Sabrina Lusvarghi, Chung-Pu Wu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
ATP Binding Cassette Transporter
Subfamily B Receptor Platelet-Derived Growth Factor alpha Cell Survival medicine.drug_class Pharmaceutical Science Apoptosis Microbial Sensitivity Tests 02 engineering and technology PDGFRA Transfection 030226 pharmacology & pharmacy Article Tyrosine-kinase inhibitor 03 medical and health sciences 0302 clinical medicine Growth factor receptor Cell Line Tumor Drug Discovery medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Protein Kinase Inhibitors P-glycoprotein biology business.industry 021001 nanoscience & nanotechnology Drug Resistance Multiple Neoplasm Proteins Molecular Docking Simulation Multiple drug resistance Proto-Oncogene Proteins c-kit Drug repositioning HEK293 Cells Drug Resistance Neoplasm Cancer cell Cancer research biology.protein Molecular Medicine 0210 nano-technology business Tyrosine kinase Protein Binding Signal Transduction |
| Zdroj: | Mol Pharm |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/acs.molpharmaceut.9b00274 |
| Popis: | The frequent occurrence of multidrug resistance (MDR) conferred by the overexpression of ATP-binding cassette (ABC) transporters ABCB1 and ABCG2 in cancer cells remains a therapeutic obstacle for scientists and clinicians. Consequently, developing or identifying modulators of ABCB1 and ABCG2 that are suitable for clinical practice is of great importance. Therefore, we have explored the drug repositioning approach to identify candidate modulators of ABCB1 and ABCG2 from tyrosine kinase inhibitors with known pharmacological properties and anticancer activities. In this study, we discovered that avapritinib (BLU-285), a potent, selective, and orally bioavailable tyrosine kinase inhibitor against mutant forms of KIT and platelet-derived growth factor receptor alpha (PDGFRA), attenuates the transport function of both ABCB1 and ABCG2. Moreover, avapritinib restores the chemosensitivity of ABCB1- and ABCG2-overexpressing MDR cancer cells at nontoxic concentrations. These findings were further supported by results of apoptosis induction assays, ATP hydrolysis assays, and docking of avapritinib in the drug-binding pockets of ABCB1 and ABCG2. Altogether, our study highlights an additional action of avapritinib on ABC drug transporters, and a combination of avapritinib with conventional chemotherapy should be further investigated in patients with MDR tumors. |
| Databáze: | OpenAIRE |
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