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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Pujol‐Giménez Jonai, Poirier Marion, Bühlmann Sven, Schuppisser Céline, Bhardwaj Rajesh, Awale Mahendra, Visini Ricardo, Javor Sacha, Hediger Matthias A., Reymond Jean‐Louis,
Project Chemical Space Design of Small Molecules and Peptides
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Original article (peer-reviewed)

Journal ChemMedChem
Volume (Issue) 16(21)
Page(s) 3306 - 3314
Title of proceedings ChemMedChem
DOI 10.1002/cmdc.v16.21

Open Access

URL http://doi.org/10.1002/cmdc.v16.21
Type of Open Access Publisher (Gold Open Access)

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.
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