Multidrug resistance protein 4 (MRP4/ABCC4) is an ATP-binding cassette (ABC) transporter. MRP4 associates with multidrug resistance (MDR), which is a growing challenge to the treatment of cancer and infections. Therefore, ATP-binding cassette transporters are capable of pumping a wide variety of endogenous and xenobiotic organic anionic compounds out of the cell.

PU 23 (Cpd23) is a novel non-carboxylic MRP4 inhibitor from virtual screening of the SPECS database, showing equivalent activity to a higher concentration of MK571 in improving cell sensibility to anticancer drug 6-MP. Especially, MRP4 functions as a prostaglandin efflux transporter.

The non-steroidal anti-inflammatory agents inhibits prostaglandin efflux transporter. As we all know, MRP4 composes of two transmembrane domains (TMDs), and two nucleotide binding domains (NBDs). In particular, MRP4/ABCC4 is a protein consisting of 1,325 amino acids encoded by the ABCC4 gene. Moreover, MRP4/ABCC4 is an ATP-dependent transporter and its main function is pumping organic anions across biological membranes against a concentration gradient.

PU 23 improves HEK293/MRP4 cell sensibility to 6-MP dramatically. In addition, PU 23 shows the highest activity with an inhibition rate of 81.71% at the concentration of 10 μM with 6-MP and only 15.26% without 6-MP. In combination with PU 23, the IC50 of 6-MP substantially decreases in MRP4 overexpressing cells. Furthermore, Preincubation of HEK293/MRP4 cells with PU 23 also significantly increases the amount of 6-MP in cells. However, preincubation of PU 23 has little effect on 6-MP accumulation in HEK293 cells.

To summarise, PU 23 is a non-carboxylic MRP4 inhibitor showing higher efficacy relative to MK571. PU 23 acts as an active agent reducing resistance to 6-Mercaptopurine (6-MP).

Ya Chen, et al. Discovery of novel multidrug resistance protein 4 (MRP4) inhibitors as active agents reducing resistance to anticancer drug 6-Mercaptopurine (6-MP) by structure and ligand-based virtual screening. PLoS One. 2018 Oct 15;13(10):e0205175.