title: Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2.
abstract: Divalent metal transporter-1 (SLC11A2/DMT1) uses the H(+) electrochemical gradient as the driving force to transport divalent metal ions such as Fe(2+), Mn(2+) and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H(+)-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H(+)-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment.
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland. Electronic address: montalbettin@gmail.com.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Montalbetti
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland. Electronic address: alexander.simonin@ibmm.unibe.ch.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Simonin
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Simonin
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Awale
authors.affiliation: Department of Chemistry and Biochemistry, University of Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland. Electronic address: jean-louis.reymond@dcb.unibe.ch.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
authors.affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland; Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland. Electronic address: matthias.hediger@ibmm.unibe.ch.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Hediger
mesh_terms: D001692:Biological Transport; D002413:Cations, Divalent; D062313:Databases, Pharmaceutical; D055808:Drug Discovery; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007501:Iron / Q000737:chemistry*; D007536:Isomerism; D007700:Kinetics; D008024:Ligands; D008345:Manganese / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry*; D011744:Pyrimidinones / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry*; D013890:Thiourea / Q000737:chemistry*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D014584:User-Computer Interface
chemical_list: D002413:Cations, Divalent; C110547:DMRT1 protein; D008024:Ligands; D011720:Pyrazoles; D011744:Pyrimidinones; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; D008345:Manganese; D007501:Iron; D013890:Thiourea
keywords: DMT1; Drug screening; Non-competitive inhibitor; SLC11A2; [2-[2-(Carbamimidoylsulfanylmethyl)phenoxy]phenyl]methyl carbamimidothioate (PubChem CID: 25070872); [3-(Carbamimidoylsulfanylmethyl)-2,4,6-trimethylphenyl]methyl carbamimidothioate (PubChem CID: 45108473); [6-(Carbamimidoylsulfanylmethyl)-8-fluorodibenzofuran-4-yl]methyl carbamimidothioate (PubChem CID: 24896381)