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

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Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-06-02 , DOI: 10.1039/d0md00085j
Marion Poirier ₁ , Jonai Pujol-Giménez _{2,

3,

4} , Cristina Manatschal ₅ , Sven Bühlmann ₁ , Ahmed Embaby ₁ , Sacha Javor ₁ , Matthias A Hediger _{2,

3,

4} , Jean-Louis Reymond ₁

Affiliation

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.

中文翻译：

吡唑基嘧啶酮通过金属螯合抑制人溶质载体蛋白 SLC11A2 (hDMT1) 的功能

溶质载体蛋白 (SLC) 控制跨生物膜的离子和分子通量，代表一类新兴的药物靶点。 SLC11A2 (hDMT1) 介导肠道铁吸收，其抑制作用可用于治疗铁过载疾病，例如遗传性血色素沉着症。在这里，我们报告了一种微摩尔（IC ₅₀ = 1.1 μM）吡唑基嘧啶酮抑制剂，通过非竞争性机制作用于过表达 hDMT1 的 HEK293 细胞中放射性标记的铁摄取，但不会影响转运蛋白的电生理特性。等温滴定量热法、与钙黄绿素的竞争、放射性铁的诱导沉淀以及不相关的铁转运蛋白 SLC39A8 (hZIP8) 的交叉抑制表明抑制是由金属螯合介导的。绘制 ChEMBL 中数千种吡唑并嘧啶酮和类似 2,2'-二氮杂二芳基化合物的化学空间表明，它们报道的活性可能部分反映了金属螯合。此类金属螯合基团未列在泛测定干扰化合物 (PAINS) 中，但在处理 SLC 时应进行检查。

更新日期：2020-06-02

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