AST1306, a potent EGFR inhibitor, antagonizes ATP-binding cassette subfamily G member 2-mediated multidrug resistance
Abstract
AST1306, an inhibitor of EGFR and ErbB2, is currently in phase I of clinical trials. We evaluated the effect of AST306 on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters. We found that AST1306 significantly sensitized the ABC subfamily G member 2 (ABCG2)-overexpressing cells to ABCG2 substrate chemotherapeutics. AST1306 significantly increased intracellular accumulation of [(3)H]-mitoxantrone in ABCG2-overexpressing cells by blocking ABCG2 efflux function. Moreover, AST1306 stimulated the ATPase activity of ABCG2. Homology modeling predicted the binding conformation of AST1306 to be within the transmembrane region of ABCG2. In conclusion, AST1306 could notably reverse ABCG2-mediated MDR.
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Allitinib effectively inhibits the EGFRT790M/L858R double mutant with an IC50 value of 12 nM.
“Allitinib effectively inhibits the EGFRT790M/L858R double mutant with an IC50 value of 12 nM.177–181”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [181]
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- Authors
- Zhang, H., Wang, Y.-J., Zhang, Y.-K., Wang, D.-S., Kathawala, R. J., Patel, A., Talele, T. T., Chen, Z.-S., & Fu, L.-W.
- Affiliations
- St. John's University (US)
- Corresponding author
- Chen, Zhe-Sheng
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 350
- Issue
- 1-2
- Pages
- 61-68
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W1983688434
- Cited by
- 34
- References
- 47
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 4 · 2021: 2 · 2020: 1 · 2018: 6 · 2017: 5 · 2016: 3 · 2015: 6 · 2014: 5
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- EGFR inhibitors, ERBB2, ABCG2, multidrug resistance reversal, ABC transporters, drug efflux, homology modeling
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Acrylamides, Antineoplastic Agents, Biological Transport, Humans, Mitoxantrone, Neoplasm Proteins, Quinazolines, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, Erb-b2 Receptor Tyrosine Kinases, Receptor, ErbB-2, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors, Molecular Docking Simulation, ErbB Receptors
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