Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation

Poirier, Marion; Pujol-Giménez, Jonai; Manatschal, Cristina; Bühlmann, Sven; Embaby, Ahmed; Javor, Sacha; Hediger, Matthias A.; Reymond, Jean-Louis (2020). Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation. RSC Medicinal Chemistry, 11(9), pp. 1023-1031. Royal Society of Chemistry 10.1039/D0MD00085J

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Solute carrier proteins (SLCs) control fluxes of ions and molecules across biological membranes and represent an emerging class of drug targets. SLC11A2 (hDMT1) mediates intestinal iron uptake and its inhibition might be used to treat iron overload diseases such as hereditary hemochromatosis. Here we report a micromolar (IC50 = 1.1 μM) pyrazolyl-pyrimidone inhibitor of radiolabeled iron uptake in hDMT1 overexpressing HEK293 cells acting by a non-competitive mechanism, which however does not affect the electrophysiological properties of the transporter. Isothermal titration calorimetry, competition with calcein, induced precipitation of radioactive iron and cross inhibition of the unrelated iron transporter SLC39A8 (hZIP8) indicate that inhibition is mediated by metal chelation. Mapping the chemical space of thousands of pyrazolo-pyrimidones and similar 2,2′-diazabiaryls in ChEMBL suggests that their reported activities might partly reflect metal chelation. Such metal chelating groups are not listed in pan-assay interference compounds (PAINS) but should be checked when addressing SLCs.

Item Type:

Journal Article (Original Article)

Division/Institute:

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

UniBE Contributor:

Poirier, Marion; Pujol Gimenez, Jonai; Bühlmann, Sven Oliver; Javor, Sacha; Hediger, Matthias and Reymond, Jean-Louis

Subjects:

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

ISSN:

2632-8682

Publisher:

Royal Society of Chemistry

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

29 Dec 2020 12:27

Last Modified:

29 Dec 2020 12:35

Publisher DOI:

10.1039/D0MD00085J

BORIS DOI:

10.48350/148852

URI:

https://boris.unibe.ch/id/eprint/148852

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