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Title: Discovery of novel symmetrical 1,4-Dihydropyridines as inhibitors of multidrug-resistant protein (MRP4) efflux pump for anticancer therapy
Author(s): Döring, Henry
Kreutzer, David
Ritter, ChristophLook up in the Integrated Authority File of the German National Library
Hilgeroth, AndreasLook up in the Integrated Authority File of the German National Library
Issue Date: 2021
Type: Article
Language: English
Abstract: Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.
Open Access: Open access publication
License: (CC BY 4.0) Creative Commons Attribution 4.0(CC BY 4.0) Creative Commons Attribution 4.0
Sponsor/Funder: Publikationsfonds MLU
Journal Title: Molecules
Publisher: MDPI
Publisher Place: Basel
Volume: 26
Issue: 1
Original Publication: 10.3390/molecules26010018
Appears in Collections:Open Access Publikationen der MLU

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