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Multidrug resistance protein 4 (MRP4) is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of actively pumping a wide variety of organic anionic compounds across the plasma membrane against their concentration gradient. In addition to transporting a wide variety of antibiotic, antiviral, cancer and cardiovascular drugs, MRP4 has the remarkable ability to transport molecules involved in cellular signaling. These molecules include eicosanoids prostaglandin E2, leukotriene B4 and thromboxane TXB2, second messengers cAMP and cGMP, as well as bile acids, conjugated steroids, and folic acid.
Upregulation of MRP4 has been implicated in the development of multiple forms of cancer, and has been proposed as an attractive therapeutic target. Whilst the function of MRP4 has been advanced by MRP4-/- mice and RNAi, until now the absence of specific small molecule inhibitors of MRP4 has been a major constraint. Other major small molecule inhibitors used to study MRP4 activity (including MK-571, dipyridamole and indomethacin) also target other related ABC transporter family members or inhibit the production, function or degradation of important MRP4 substrates.
In light of these limitations, a group led by Prof Michelle Haber and Prof Murray Norris at Australia's Children's Cancer Institute, set out and identified two chemically distinct inhibitors, Ceefourin™ 1 and Ceefourin™ 2, that are highly selective for MRP4. The authors demonstrated that these compounds inhibit the transport of a broad range of key MRP4 substrates, and that they are low in cellular toxicity and highly stable. See the full report in Biochemical Pharmacology, September 2014.
These selective MRP4 inhibitors are now exclusively available from Abcam.