P-glycoprotein (P-gp) has been considered an important molecular target in the reversal of multidrug resistance (MDR). As such, the development of P-gp modulators able to restore drug sensitivity in resistant cells is still considered one of the most promising strategies for overcoming MDR. Since the identification of the P-gp’s role in MDR, several studies have been performed in order to develop effective P-gp modulators and understand the efflux mechanism. However, no efflux modulator is still clinically available for treating multidrug-resistant cancers. Nevertheless, recent experimental studies suggest that MDR can be surpassed by targeting a specific region within the ABC transporter structure rather than the polyspecific drug-binding pocket. This article will focus on the information available about this new target region and on a brief overview of which scaffolds would be suitable for modulating P-gp at this new location.
Ricardo J. Ferreira 1†, Cátia A. Bonito 1,2, Maria José U. Ferreira 1*, and Daniel J. V. A. dos Santos 1,2∗
† Present address: LAQV@REQUIMTE/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre, Porto, Portugal
1 Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
2 LAQV@REQUIMTE/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal