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J Med Chem. 2013 Feb 14;56(3):781-795. doi: 10.1021/jm301302s. Epub 2013 Jan 22.

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

Author information

1
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences RH 581, 1550 4 Street San Francisco, CA 94158, United States of America.
2
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, and California Institute for Quantitative Biosciences (QB3) BH 503B, 1700 4 Street San Francisco, CA 94158, United States of America.
3
Drug-Drug Interaction Group, Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd. 3-1-1, Futaba-cho, Toyonaka-shi Osaka 561-0825, Japan.
4
Optivia Biotechnology Inc. 115 Constitution Drive, Suite 7 Menlo Park, CA 94025.
#
Contributed equally

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.

PMID:
23241029
PMCID:
PMC4068829
DOI:
10.1021/jm301302s
[Indexed for MEDLINE]
Free PMC Article

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