Final Report Summary - ABC (Targeting Multidrug Resistant Cancer)
The overall aim of the project was to develop compounds that specifically target multidrug resistant (MDR) cancer. The central tenet is that ABCB1/Pgp, a universally accepted biomarker of drug resistance, should be considered as a molecular target of multidrug-resistant cancer cells. Using a screening platform established in the project, we identified several MDR-selective compounds that are paradoxically more toxic to otherwise multidrug resistant cells. Based on the analysis of structure-activity relationships, focused chemical libraries were synthesized around confirmed hits. As a result of an iterative approach, we obtained drug-like analogs that are significantly more toxic and more selective. Structure-activity relationships derived from the screens provided important clues for the understanding of the mechanism of toxicity. The best performing compounds were subjected to analytical, formulation, toxicity and dose finding studies. The antitumor and MDR-selective potential of the compounds was analyzed in genetically engineered models of resistant cancer.