How can we best use structural information on P-glycoprotein to design inhibitors?
This year marks the 30th anniversary of the discovery of the multidrug resistance (MDR) ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp). Since then a considerable research effort has attempted to provide a greater understanding of the biological enigma of “multidrug” efflux. Moreover, the growing correlation between P-gp expression and a negative prognosis or poor outcome for chemotherapy has sparked significant interest in the generation of inhibitors. How close are we to overcoming the unwanted actions of P-gp in resistant cancer following 30 years of research? The initial inhibitors were pre-existing clinically used compounds and exploited the broad specificity of P-gp. Unfortunately, the concentrations required to inhibit P-gp meant that these compounds generated considerable toxicity. Pharmacological investigations progressed to rational design using the 1st generation compounds as a template structure. Inherent toxicity of the drugs was reduced; however, pharmacokine
