Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol.

Plasma membrane drug efflux pumps of the multidrug resistance associated protein (MRP) family blunt the effectiveness of anticancer drugs and are often associated with drug resistance. GSAO, a tripeptide trivalent arsenical that targets a key mitochondrial transporter in angiogenic endothelial cells, is an example of a compound whose efficacy is limited by tumor cell expression of MRP isoforms 1 and 2. A cysteine mimetic analogue of GSAO was made, PENAO, which accumulates in cells 85 times faster than GSAO due to increased rate of entry and decreased rate of export via MRP1/2. The faster rate of accumulation of PENAO corresponds to a 44-fold increase in antiproliferative activity in vitro and approximately 20-fold better antitumor efficacy in vivo. This information could be used to improve the efficacy of other small molecule cancer therapeutics.