Inhibition of the Multidrug Resistance Protein 1 (MRP1) by Peptidomimetic Glutathione-Conjugate Analogs

Abstract

Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study structure-activity relationships of MRP1 inhibition, a series of novel GS-EA analogs was synthesized in which peptide bonds of the GSH backbone were replaced by isosteric groups [Bioorg Med Chem 10:195-205, 2002]. Several of these compounds were effective inhibitors of MRP1-mediated [ 3 H]GS-EA and [ 3 H]E 2 17␤G transport, as studied in membrane vesicles prepared from MRP1-overproducing Sf9 cells. The modifications of the peptide backbone have distinct implications for recognition by MRP1: the ␥-glutamyl-cysteine peptide bond is important for binding, whereas the cysteinyl-glycine amide does not seem essential. When the ␥-glutamyl-cysteine peptide bond (C-CO-N) is replaced by a urethane isostere (O-CO-N), an effective competitive MRP1-inhibitor (K i ϭ 11 M) is obtained. After esterification of this compound to improve its cellular uptake, it inhibited MRP1-mediated efflux of calcein from 2008 ovarian carcinoma cells overexpressing MRP1. This compound also partially reversed the resistance of these cells to methotrexate. Because the urethane isostere is stable toward ␥-glutamyl transpeptidase-mediated breakdown, it is an interesting lead-compound for the development of in vivo active MRP1 inhibitors.

Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients

“…However, these inhibitors are associated with undesirable side effects like liver damage [62]. The development of more specific peptidomimetic inhibitors, glutathione-conjugate analogs (MRP1 inhibitor), could prevent these adverse outcomes [63]. …”

Molecular Basis for Reduced Estrone Sulfate Transport and Altered Modulator Sensitivity of Transmembrane Helix (TM) 6 and TM17 Mutants of Multidrug Resistance Protein 1 (ABCC1)

“…Also relevant is the study of Burg et al (2002) showing that the potent inhibition of MRP1 transport activity by GSH conjugates and peptidomimetic GSH conjugate analogs is dependent on the presence of a ␥-Glu moiety.…”

Strategies for drug delivery to the central nervous system by systemic route

“…Ethacrynic acid conjugated with glutathione is found to be a potent inhibitor of MRP (Burg et al, 2002). Again as mentioned earlier, care should be exercised while blocking MRP.…”