Abstract
Tricyclic isoxazoles were identified from a screen as a novel class of selective multidrug resistance protein (MRP1) inhibitors. From a screen lead, SAR efforts resulted in the preparation of LY 402913 (9h), which inhibits MRP1 and reverses drug resistance to MRP1 substrates, such as doxorubicin, in HeLa-T5 cells (EC(50)=0.90 microM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC(4) uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC(50)=1.8 microM). LY 402913 also shows selectivity ( approximately 22-fold) against the related transporter, P-glycoprotein, in HL60/Adr and HL60/Vinc cells. Finally, when dosed in combination with the oncolytic MRP1 substrate vincristine, LY 402913 delays the growth of MRP1-overexpressing tumors in vivo.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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Antineoplastic Agents, Phytogenic / pharmacology
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Biological Transport, Active / drug effects
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Cell Division / drug effects
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Doxorubicin / pharmacology
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Drug Resistance
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Drug Synergism
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Heterocyclic Compounds, 3-Ring / chemical synthesis
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Isoxazoles / chemical synthesis*
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Isoxazoles / chemistry
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Isoxazoles / pharmacology
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Leukotriene C4 / metabolism
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Structure-Activity Relationship
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Tumor Cells, Cultured
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Vincristine / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antineoplastic Agents, Phytogenic
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Heterocyclic Compounds, 3-Ring
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Isoxazoles
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Multidrug Resistance-Associated Proteins
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Leukotriene C4
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Vincristine
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Doxorubicin
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multidrug resistance-associated protein 1