Derivative of 5-cyano-6-phenylpyrimidin antagonizes ABCB1- and ABCG2-mediated multidrug resistance.

Abstract

Multidrug resistance (MDR) leads to inadequate response to chemotherapy and cause failure in cancer treatment. One of the targeted approaches to overcome MDR in cancer cells is interfering or inhibiting ATP binding cassette (ABC) transporters. Among all members in ABC transporters superfamily, ABCB1 (ABC transporter subfamily B #1) and ABCG2 (ABC transporter subfamily G #2) play an important role in the development of cancer MDR. In this study, we synthesized a novel 5-cyano-6-phenylpyrimidin derivative 479, which exhibited selective dual-activity in reversing MDR mediated by ABCB1 and ABCG2, without affecting MDR mediated by ABCC1 (ABC transporter subfamily C #1) and ABCC10 (ABC transporter subfamily C #10). Further mechanism studies demonstrated that 479 increased the accumulation of paclitaxel and mitoxantrone in cancer cells by interrupting the efflux function of transporters and stimulating ABCB1/ABCG2 ATPase activity. In silico study provided evidence that 479 formed multiple physiochemical bonds with the drug-binding pocket of ABCB1 and ABCG2. Overall, our results provide a promising prototype in designing potent dual reversal agents targeting ABCB1- and ABCG2-meidated MDR.