Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C.

Inhibitors of the breast cancer resistance protein (BCRP/ABCG2) multidrug transporter are of interest as chemosensitizers for clinical drug resistance, for improving the pharmacokinetics of substrate chemotherapeutic drugs, and in functional assays of BCRP activity for tailoring chemotherapy. The fungal toxin fumitremorgin C (FTC) is a potent and specific inhibitor of BCRP, but its neurotoxic effects preclude use in vivo. We have therefore evaluated a new tetracyclic analogue of FTC, Ko143, as a practical inhibitor of BCRP, comparing it with two other analogues in the same class and with GF120918. All three FTC analogues are effective inhibitors of both mouse Bcrp1 and human BCRP, proving highly active for…