MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine substrate binding sites as a tool for drug design

GOMEZ N; SHAYO C; SAHORES A; CAROZZO A; YANEFF A; DI SIERVI N; DAVIO C

Buenos Aires

Congreso; Reunión Conjuntas de Sociedades de Biociencias; 2017

SAIC

Over the last years, numerous MRP transporters have been suggested as possible pharmacological targets for the treatment of cancer for several reasons: their increased expression in tumor cells, their ability to generate multidrug resistance and transport of endogenous substrates that can eventually increase tumor malignancy. Due to the structural complexity of their substrate binding pocket, designing specific pharmacological agents with the ability to selectively modify their affinity to certain substrates represents a challenge in current medicinal chemistry. We have recently established that inhibiting cAMP extrusion by MRP4 could represent a possible effective therapeutic strategy for PDAC and AML. Using available information regarding substrate specificity, homology models, mutagenesis assays and pharmacological inhibitors we recapitulate the up-to-date knowledge about MRP4 structure. We also aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides may bind. We identified two possible binding sites that are present both in the outward and inward conformation of the transporter and developed a map of inhibitors of MRP4 endogenous substrates