The Novel Calcineurin Inhibitor CN585 Has Potent Immunosuppressive Properties in Stimulated Human T Cells |
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Authors: | Frank Erdmann Matthias Weiwad Susann Kilka Magdalena Karanik Michael P?tzel Ria Baumgrass Jürgen Liebscher Gunter Fischer |
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Affiliation: | From the ‡Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, ;the §Department of Chemistry, Humboldt University Berlin, Brook-Taylor-Strasse 2, D-12489 Berlin, and ;¶Deutsches Rheuma-Forschungszentrum Berlin, Schumannstrasse 21/22, D-10117 Berlin, Germany |
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Abstract: | The Ca2+/calmodulin-dependent protein phosphatase calcineurin is a key mediator in antigen-specific T cell activation. Thus, inhibitors of calcineurin, such as cyclosporin A or FK506, can block T cell activation and are used as immunosuppressive drugs to prevent graft-versus-host reactions and autoimmune diseases. In this study we describe the identification of 2,6- diaryl-substituted pyrimidine derivatives as a new class of calcineurin inhibitors, obtained by screening of a substance library. By rational design of the parent compound we have attained the derivative 6-(3,4-dichloro-phenyl)-4-(N,N-dimethylaminoethylthio)-2-phenyl-pyrimidine (CN585) that noncompetitively and reversibly inhibits calcineurin activity with a Ki value of 3.8 μm. This derivative specifically inhibits calcineurin without affecting other Ser/Thr protein phosphatases or peptidyl prolyl cis/trans isomerases. CN585 shows potent immunosuppressive effects by inhibiting NFAT nuclear translocation and transactivation, cytokine production, and T cell proliferation. Moreover, the calcineurin inhibitor exhibits no cytotoxicity in the effective concentration range. Therefore, calcineurin inhibition by CN585 may represent a novel promising strategy for immune intervention. |
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Keywords: | Calcium/Calcineurin Enzymes Enzymes/Inhibitors Immunology/Humoral response/Immunosupressor/Immunophilin Immunology/Humoral response/NFAT Phosphorylation/Phosphatases/Serine-Threonine Phosphorylation/Serine/Threonine Protein/Drug Interactions |
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