Discovery of Potent, Selective Multidrug and Toxin Extrusion Transporter 1 (MATE1, SLC47A1) Inhibitors Through Prescription Drug Profiling and Computational Modeling

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.