Recent advances in the search of BCRP- and dual P-gp/BCRP-based multidrug resistance modulators

Abstract

The development of multidrug resistance (MDR) is one of the major challenges to the success of chemotherapy treatment of cancer. This phenomenon is often associated with the overexpression of the ATP-binding cassette (ABC) transporters P-gp (P-glycoprotein, ABCB1), multidrug resistance-associated protein 1, ABCC1 and breast cancer resistance protein, ABCG2 (BCRP). These transporters are constitutively expressed in many tissues playing relevant protective roles by the regulation of the permeability of biological membranes, but they are also overexpressed in malignant tissues. P-gp is the first efflux transporter discovered to be involved in cancer drug resistance, and over the years, inhibitors of this pump have been disclosed to administer them in combination with chemotherapeutic agents. Three generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate that coadministration of pump inhibitors elicits an improvement in therapeutic efficacy of antitumor agents, although some of the latest compounds show better results. Therefore, new and innovative strategies, such as the fallback to natural products and the discover of dual activity ligands emerged as new perspectives. BCRP is the most recently ABC protein identified to be involved in multidrug resistance. It is overexpressed in several haematological and solid tumours together with P-gp, threatening the therapeutic effectiveness of different chemotherapeutic drugs. The chemistry of recently described BCRP inhibitors and dual P-gp/BCRP inhibitors, as well as their preliminary pharmacological evaluation are discussed, and the most recent advances concerning these kinds of MDR modulators are reviewed.

Keywords: ATP-binding cassette transporter inhibitors; Cancer; P-glycoprotein; breast cancer resistance protein; multidrug resistance; multidrug resistance modulators; multidrug resistance-associated proteins.

Figure 1

Schematic picture of the secondary structure of the ABC family drug transporters P-gp, MRP1 and BCRP. NBD: nucleotide binding domains

Figure 2

The inward-facing exporter binds substrate (D, drug) from the cytoplasm or the inner leaflet of the bilayer. After binding two molecules of MgATP, the nucleotide-binding domains (NBDs) dimerize and switch the transmembrane domain (TMDs) from the inward- to the outward-facing conformation, followed by the release of the drug to the extracellular environment. ATP hydrolysis, ADP/Pi release and NBD dissociation reset the transporter to the inward-facing conformation. The figure is quoted with permission from Wilkens^[47].

Figure 3

Flavonoids and chromone derivatives

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Chalcone derivatives

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Chalcone quinazoline derivatives

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Acryloylphenylcarboxamide derivatives

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Chalcone and flavone derivatives

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Schizandrin derivatives

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Curcumin derivatives

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Quinazoline and quinoline derivatives

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Tariquidar derivatives

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HM30181 derivatives

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Tetrazole derivatives

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Sulfonamido derivatives of tariquidar

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Triazole derivatives

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Chalcone and ketone derivatives of tariquidar

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Aryl-substituted derivatives of tariquidar

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Tetrahydro-β-carboline derivatives

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5-Oxo-hexahydroquinoline derivatives

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9-Deazapurine derivatives

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Homoverrucosanoid derivatives

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Propafenone derivatives

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HIF-1 inhibitor

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Ester derivative