Specific Inhibitors of the Breast Cancer Resistance Protein (BCRP)

Abstract

A new class of specific breast cancer resistance protein (BCRP) inhibitors was identified, showing no inhibition of the ATP binding cassette (ABC) transporters P-gp and MRP1. Some of these modulators inhibit BCRP with high potency; they are only slightly less potent than Ko143 and could serve as promising lead structures for the design of novel effective BCRP inhibitors. These inhibitors are structurally related to tariquidar (XR9576) and belong to a library of multidrug-resistance modulators synthesized by our research group. The absence of the tetrahydroisoquinoline substructure appears to play a crucial role for specificity; we found that the presence of this substructure is not essential for interaction with BCRP. To determine the type of interaction between pheophorbide A and compounds with and without the tetrahydroisoquinoline substructure, various substrate pheophorbide A concentrations were used in enzyme kinetics assays. The resulting data show that these compounds share a noncompetitive-type interaction with pheophorbide A. Experiments with imatinib and pheophorbide A revealed a mixed-type interaction. The combination of imatinib and compounds with and without the tetrahydroisoquinoline substructure resulted in a positive cooperative effect, indicating that imatinib engages a binding site distinct from that of the new compounds on one side and distinct from that of pheophorbide A on the other side as well. The results of this study suggest that the category of BCRP-specific inhibitors, which includes only fumitremorgin C, Ko143 and analogues, and novobiocin needs to be extended by this new class of inhibitors, which possess three key characteristics: specificity, potency, and low toxicity.

The short-chain fatty acid butyrate is a substrate of breast cancer resistance protein

“…Two examples of such interaction are given next. First, BCRP acts as an efflux transporter for various anticancer agents including 5-fluorouracil, methotrexate, mitoxantrone, anthracyclines, daunorubicin, doxorubicin, topotecan, diflomotecan, irinotecan, tyrosine kinase inhibitors (e.g., imatinib and gefitinib), and nucleoside analogs (49,52). Thus it prevents the buildup of high intracellular concentrations of such anticancer agents and decreases their cytotoxic effects.…”

UDP-Glucuronosyltransferase (UGT) 1A9-Overexpressing HeLa Cells Is an Appropriate Tool to Delineate the Kinetic Interplay between Breast Cancer Resistance Protein (BRCP) and UGT and to Rapidly Identify the Glucuronide Substrates of BCRP

“…Effects of Ko143 on the Excretion of Glucuronides. Next, the role of BCRP in excretion of glucuronides in the engineered HeLa cells was determined, using a specific and potent chemical inhibitor, Ko143 (Pick et al, 2010) (Fig. 6).…”

Scaffold Identification of a New Class of Potent and Selective BCRP Inhibitors

“…The inhibitory activities of the tested derivatives showed ah igh correlation, in agreement with the results obtained for asmaller set of derivatives containing ah ydroxyethyl side chain. [17] The correlation between IC 50 values in both test systems is shown in Figure 4.…”

“…[16] Structural modification of XR9576, with deletion of the tetrahydroisoquinoline group, led to compounds that were shown to be selective BCRP inhibitors. [17] In our previous work [18] we investigated the structure-activity relationships forc ompounds of this new class with modifications on the aromatic rings Ba nd Co ft he originals caffold ( Figure 1). The aim of this study is to investigate the importance of modifications on aromatic ring Ai n order to better define am inimum scaffold for of this new BCRP inhibitor class.…”