In cancer, therapy can be as debilitating as the disease. Current treatments are often accompanied by severe toxicities in patients. These toxicities prompt continuing investigation into new therapies with reduced or preferentially no toxic effects. While treating cancer cells without toxicity to normal cells is the goal of drug discovery, the task itself has met with limited success due to the difficulty of distinguishing cancer cells from normal cells. In our work, we use tumor copper load as a physiological difference between cancer cells and normal cells and to design compounds that are benign in the absence of elevated cellular copper. The purpose of these compounds is to mobilize endogenous tumor copper resulting in in cellulo activation of a compound capable of inhibiting the proteasome within cancer cells
Virtual Screening of various databases is employed to search for compounds that can chelate copper ions and simultaneously inhibit the 20S proteasasome as shown in the figure. In the figure, the copper ion is depicted as a cyan sphere. The gray blur shows multiple "virtual hits" docked to the chymotrypsin-like active site of the 20S proteasome.