Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.

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Wittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X, Morrissey KM, Sali A, Huang Y, Giacomini KM

Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.

J Med Chem. 2013 Feb 14;56(3):781-95. doi: 10.1021/jm301302s. Epub 2013 Jan 22.

PubMed ID
23241029 [ View in PubMed
]
Abstract

The human multidrug and toxin extrusion (MATE) transporter 1 contributes to the tissue distribution and excretion of many drugs. Inhibition of MATE1 may result in potential drug-drug interactions (DDIs) and alterations in drug exposure and accumulation in various tissues. The primary goals of this project were to identify MATE1 inhibitors with clinical importance or in vitro utility and to elucidate the physicochemical properties that differ between MATE1 and OCT2 inhibitors. Using a fluorescence assay of ASP(+) uptake in cells stably expressing MATE1, over 900 prescription drugs were screened and 84 potential MATE1 inhibitors were found. We identified several MATE1 selective inhibitors including four FDA-approved medications that may be clinically relevant MATE1 inhibitors and could cause a clinical DDI. In parallel, a QSAR model identified distinct molecular properties of MATE1 versus OCT2 inhibitors and was used to screen the DrugBank in silico library for new hits in a larger chemical space.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
TopotecanMultidrug and toxin extrusion protein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
FamotidineSolute carrier family 22 member 2IC 50 (nM)36100N/AN/ADetails
ImatinibSolute carrier family 22 member 1IC 50 (nM)107000N/AN/ADetails
ImatinibSolute carrier family 22 member 2IC 50 (nM)4200N/AN/ADetails
IndinavirSolute carrier family 22 member 1IC 50 (nM)208000N/AN/ADetails
IrinotecanSolute carrier family 22 member 3IC 50 (nM)74600N/AN/ADetails
MetforminMultidrug and toxin extrusion protein 1IC 50 (nM)250000N/AN/ADetails
TubocurarineSolute carrier family 22 member 2IC 50 (nM)78800N/AN/ADetails