Author/Authors :
Bryan H. Norman، نويسنده , , Joseph M. Gruber، نويسنده , , Sean P. Hollinshead، نويسنده , , Joseph W. Wilson، نويسنده , , James J. Starling، نويسنده , , Kevin L. Law، نويسنده , , Tracy D. Self، نويسنده , , Linda B. Tabas، نويسنده , , Daniel C. Williams، نويسنده , , Donald C. Paul، نويسنده , , Margaret M. Wagner، نويسنده , , Anne H. Dantzig، نويسنده ,
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 (EC50=0.90 μM), while showing no inherent cytotoxicity. Additionally, LY 402913 inhibits ATP-dependent, MRP1-mediated LTC4 uptake into membrane vesicles prepared from the MRP1-overexpressing HeLa-T5 cells (EC50=1.8 μM). LY 402913 also shows selectivity ( 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.
