Discovery of Potent Inhibitors for Breast Cancer Multidrug Resistance

摘要

The development of MDR in metastatic breast cancer is the primary cause of failure in the current chemotherapy treatment regimens. Although the precise nature of this clinical phenomenon is unclear and is likely due to several factors, the majority of breast tumors, like several other cancers, acquire resistance by multidrug efflux pumps. Several inhibitors (like Novartis compound PSC833) have already been discovered targeting both human MDR transporters. These MDR reversing agents however have been lacking in their potencies and their mechanism of action has been unknown. We have applied a highly integrated and innovative approach for the discovery of potent MDR inhibitors of breast cancer MDR by combining the most cutting-edge methods in chemical synthesis, drug discovery, and molecular structure. We have implemented click chemistry to produce a library of inhibitors, (2) developed functional assays, and (3) determined the structure of a close ortholog of hMDR1 with these anti-cancer compounds.