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

Pujol-Giménez, Jonai; Poirier, Marion; Bühlmann, Sven; Schuppisser, Céline; Bhardwaj, Rajesh; Awale, Mahendra; Visini, Ricardo; Javor, Sacha; Hediger, Matthias; Reymond, Jean-Louis (2021). Inhibitors of Human Divalent Metal Transporters DMT1 (SLC11A2) and ZIP8 (SLC39A8) from a GDB-17 Fragment Library. ChemMedChem, 16(21), pp. 3306-3314. Wiley-VCH 10.1002/cmdc.202100467

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Nephrologie / Hypertonie
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Pujol Gimenez, Jonai; Poirier, Marion; Bühlmann, Sven Oliver; Schuppisser, Céline Delia; Bhardwaj, Rajesh; Awale, Mahendra; Visini, Ricardo; Javor, Sacha; Hediger, Matthias and Reymond, Jean-Louis

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1860-7179

Publisher:

Wiley-VCH

Language:

English

Submitter:

Verena de Serra Frazao-Bill

Date Deposited:

19 Jan 2022 11:17

Last Modified:

19 Jan 2022 11:22

Publisher DOI:

10.1002/cmdc.202100467

PubMed ID:

34309203

Uncontrolled Keywords:

chemical space fragments inhibitors iron transport membrane transporters

BORIS DOI:

10.48350/162878

URI:

https://boris.unibe.ch/id/eprint/162878

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