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

Abstract

Dedicated to the memory of Prof. François DiederichSolute 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.

Ferroptosis in non-alcoholic liver disease: Molecular mechanisms and therapeutic implications

“…In addition, an increased level of the iron-import protein DMT1 was observed in NAFLD subjects, and some DMT1 inhibitors have been designed ( 146 ). However, in the treatment of NAFLD, these inhibitors could not exert satisfactory effects ( 148 ). Therefore, great efforts are warranted to develop more effective inhibitors targeting iron-import proteins and enhancers targeting iron-export proteins, which can reduce intestinal iron absorption and block ferroptosis, thus conferring protection against NAFLD.…”

Zinc in Cardiovascular Functions and Diseases: Epidemiology and Molecular Mechanisms for Therapeutic Development

“…A ZIP8 inhibitor, (S)-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine was identified by Cd 2+ -uptake assay in the cells transiently expressing ZIP8 (IC 50 = 17.2 μM). This compound showed cross reactivity to two zinc transporters ZIP2 and ZIP14, and to four membrane proteins, serotonin receptor (5-HT2A), dopamine transporter, serotonin transporter and ERG potassium channel [ 71 ]. As food ingredients that can affect the expression of zinc transporter, soyasaponin Bb which is extracted from soybeans decreased zinc-induced mouse ZIP4 (mZIP4) endocytosis and increased the protein expression of both mouse and human ZIP4 and the intracellular zinc levels [ 72 ].…”

Mineral metabolism and ferroptosis in non-alcoholic fatty liver diseases

“…Therefore, restricting dietary iron supplements or inhibiting iron absorption could be a potential therapeutic option for iron overload diseases [75]. Hence, several DMT1 inhibitors have been designed [76] , but their efficacy is still awaiting elucidation, especially in NAFLD-related liver diseases. In addition, protecting intestinal epithelial cells from inflammatory injury [39] and maintaining gut microbiome homeostasis [77] are potential therapeutic strategies.…”