The novel calcineurin inhibitor CN585 has potent immunosuppressive properties in stimulated human T cells.

The Journal of Biological Chemistry
Frank ErdmannGunter Fischer

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 K(i) value of 3.8 mum. 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 in...Continue Reading

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Citations

Sep 11, 2014·Human Molecular Genetics·Maud GratuzeEmmanuel Planel
Jul 10, 2015·ACS Infectious Diseases·Christopher F HarrisonHubert Hilbi
Oct 29, 2009·Cell Communication and Signaling : CCS·Matthias Sieber, Ria Baumgrass
Mar 11, 2005·FEBS Letters·Matthias WeiwadGunter Fischer
May 30, 2019·American Journal of Physiology. Renal Physiology·Mohammed M NoohSuleiman W Bahouth
Sep 6, 2019·Scientific Reports·Takahiro GoshimaMidori Shimada
Feb 18, 2014·The Journal of Biological Chemistry·Kassandra Weber, Joel D Schilling
Oct 20, 2020·Journal of Medicinal Chemistry·Patrick G DoughertyDehua Pei

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