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ID: ALA1135242
Journal: Bioorg Med Chem Lett
Title: Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1).
Authors: Norman BH, Gruber JM, Hollinshead SP, Wilson JW, Starling JJ, Law KL, Self TD, Tabas LB, Williams DC, Paul DC, Wagner MM, Dantzig AH.
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.
CiteXplore: 11958985