title: Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling.
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.
authors.affiliation: University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences RH 581, 1550 4 Street San Francisco, CA 94158, United States of America.
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Wittwer
authors.affiliation: University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences RH 581, 1550 4 Street San Francisco, CA 94158, United States of America.
authors.forename: Arik A
authors.initials: AA
authors.lastname: Zur
authors.affiliation: 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.
authors.forename: Natalia
authors.initials: N
authors.lastname: Khuri
authors.affiliation: Drug-Drug Interaction Group, Drug Metabolism and Pharmacokinetics, Shionogi & Co., Ltd. 3-1-1, Futaba-cho, Toyonaka-shi Osaka 561-0825, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kido
authors.affiliation: Optivia Biotechnology Inc. 115 Constitution Drive, Suite 7 Menlo Park, CA 94025.
authors.forename: Alan
authors.initials: A
authors.lastname: Kosaka
authors.affiliation: Optivia Biotechnology Inc. 115 Constitution Drive, Suite 7 Menlo Park, CA 94025.
authors.forename: Xuexiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences RH 581, 1550 4 Street San Francisco, CA 94158, United States of America.
authors.forename: Kari M
authors.initials: KM
authors.lastname: Morrissey
authors.affiliation: 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.
authors.forename: Andrej
authors.initials: A
authors.lastname: Sali
authors.affiliation: Optivia Biotechnology Inc. 115 Constitution Drive, Suite 7 Menlo Park, CA 94025.
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.affiliation: University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences RH 581, 1550 4 Street San Francisco, CA 94158, United States of America.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Giacomini
mesh_terms: D003198:Computer Simulation; D005456:Fluorescent Dyes; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors*; D055553:Prescription Drugs
chemical_list: D005456:Fluorescent Dyes; D027701:Organic Cation Transport Proteins; D055553:Prescription Drugs; C521869:SLC47A1 protein, human