Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB‐17 Fragment Library. (31st August 2021)

• Record Type: Journal Article
• Authors: Pujol‐Giménez, Jonai; Poirier, Marion; Bühlmann, Sven; Schuppisser, Céline; Bhardwaj, Rajesh; Awale, Mahendra; Visini, Ricardo; Javor, Sacha; Hediger, Matthias A.; Reymond, Jean‐Louis
• Is Part Of: ChemMedChem. Volume 16:Number 21(2021)
• Page Start: 3306
• Page End: 3314
• Publication Date: 2021-08-31
• Subjects: membrane transporters -- fragments -- chemical space -- inhibitors -- iron transport; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202100467
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Solute carrier proteins (SLCs) are membrane proteins controlling fluxes across biological membranes and represent an emerging class of drug targets. Here we searched for inhibitors of divalent metal transporters in a library of 1, 676 commercially available 3D‐shaped fragment‐like molecules from the generated database GDB‐17, which lists all possible organic molecules up to 17 atoms of C, N, O, S and halogen following simple criteria for chemical stability and synthetic feasibility. While screening against DMT1 (SLC11A2), an iron transporter associated with hemochromatosis and for which only very few inhibitors are known, only yielded two weak inhibitors, our approach led to the discovery of the first inhibitor of ZIP8 (SLC39A8), a zinc transporter associated with manganese homeostasis and osteoarthritis but with no previously reported pharmacology, demonstrating that this target is druggable. Abstract : Transport restrictions : Screening a library of 1, 676 commercially available fragments from the database GDB‐17 revealed two weak inhibitors of DMT1, an iron transporter associated with hemochromatosis, and the first inhibitor of ZIP8, a zinc transporter associated with manganese homeostasis and osteoarthritis.