10 February 2025
The human ATP-binding cassette transporter subfamily C (ABCC) consists of 12 integral membrane proteins. Among them, nine proteins (ABCC1-ABCC6, ABCC10-ABCC12) form the multidrug resistance protein subfamily. These MRP proteins are widely expressed in the body. MRP4, for instance, is expressed in various tissues and organs, including the brain, liver, and kidney. Functionally, MRP4 serves as an ATP-dependent efflux transporter and modulates cyclic nucleotide levels such as cAMP and cGMP. The latter are involved in cellular processes such as proliferation, apoptosis, and inflammation. MRP4 proteins also export toxic agents and metabolites, aiding in cellular detoxification and maintaining cellular homeostasis.
In astrocytes of the central nervous system, MRP4 reduces intracellular cGMP levels, releases cAMP and cGMP into the extracellular space, controls intracellular pH, inhibits cellular responses of cerebellar neurons mediated by kainate receptors, and protects against glutamate-induced toxicity.
In the liver, MRP4 mediates the efflux of glutathione (GSH) from hepatocytes into the blood by co-transport with monoanionic bile salts. This process serves as an antioxidant, provides cysteine for other organs, and acts as an overflow pathway during impaired bile salt secretion into bile.
MRP4 proteins are implicated in drug resistance in certain cancers. They facilitate the efflux of chemotherapeutic agents, reducing their intracellular concentration and potentially impacting their effectiveness.
With BI-4926, we now provide a potent and selective MRP4 inhibitor. This molecule and its inactive analogue BI-5106 are available via opnMe for investigating the roles of MRP4 and they are also suitable for in vivo experiments. Interested researchers will receive the molecule free of charge and own their results.
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About BI-4926:
BI-4926 is a potent small-molecule inhibitor of multidrug resistance protein 4 (MRP4) that can be used for in vitro or in vivo testing. In assays measuring cAMP flux, BI-4926 displayed a double-digit nanomolar in vitro potency. The MRP4 inhibitor is highly permeable and binds strongly to plasma proteins. It has low risks for interaction with drug-metabolizing enzymes of the cytochrome P450 superfamily. The structurally related inactive analogue BI-5106 serves as a negative control.
About opnMe:
opnMe.com, the open innovation portal of Boehringer Ingelheim, fosters science and collaboration initiatives in areas of high unmet medical need. As part of our first pillar, the “Molecules to Order”, we share well-characterized tool compounds free of charge with no IP strings attached. These are complemented by “Molecules for Collaboration” where we offer access to unprecedented, often unpublished molecules, together with an attractive funding package. Interested scientists are invited to submit testable research hypotheses with these assets in novel diseases or combinations. With our “opn2EXPERTS” and “techMATCH” programs, we enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs. Our opn2TALENTS PostDoc grants, such as our recent call for proposals to optimize a poxvirus-based cancer vaccine platform, provide an opportunity for high-caliber talents to pitch their scientific approaches for well-defined research questions to conduct their research at one of our discovery research sites.