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Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances
Author(s) -
Stefan Sven Marcel,
Wiese Michael
Publication year - 2019
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/med.21510
Subject(s) - multiple drug resistance , abcc1 , efflux , small molecule , function (biology) , intracellular , pharmacology , computational biology , transporter , biology , atp binding cassette transporter , drug resistance , chemistry , biochemistry , gene , microbiology and biotechnology , genetics
Multidrug resistance‐associated protein 1 (MRP1, ABCC1) is an ATP‐binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high‐throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1‐mediated MDR, from the time of its discovery until today. The focus lies on small‐molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1‐overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1‐related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1‐mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad‐spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.