Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 3, Pages 781-795Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm301302s
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Funding
- National Institute of General Medical Sciences (NIGMS) [R44 GM086970, U01 GM61390, U54 GM074929]
- The Swiss National Science Foundation [PBBSP3-133384]
- FDA-CEDER/ORISE
- NIH, FDA-CDER/ORISE [T32 GM007175]
- Swiss National Science Foundation (SNF) [PBBSP3-133384] Funding Source: Swiss National Science Foundation (SNF)
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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 Drug Bank in silico library for new hits in a larger chemical space.
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