ArticleThe Journal of biological chemistry2010
The novel calcineurin inhibitor CN585 has potent immunosuppressive properties in stimulated human T cells.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 33 citations in OpenAlex.
- Calcineurin/NFATc1 pathway represses cellular cytotoxicity by modulating histone H3 expression.Scientific reports · 2024Article
- Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal PathogenJournal of fungi (Basel, Switzerland) · 2022Article
- Calcineurin dephosphorylates topoisomerase IIβ and regulates the formation of neuronal-activity-induced DNA breaks.Molecular cell · 2022Article
- Development of a novel pharmacophore model to screen specific inhibitors for the serine-threonine protein phosphatase calcineurin.Biochemistry and biophysics reports · 2022Article
- The Identification of a Novel Calcium-Dependent Link Between NADFrontiers in molecular biosciences · 2021Article
- A Peptidyl Inhibitor that Blocks Calcineurin-NFAT Interaction and Prevents Acute Lung Injury.Journal of medicinal chemistry · 2020Article
- Calcineurin regulates cyclin D1 stability through dephosphorylation at T286.Scientific reports · 2019Article
- Involvement of PDZ-SAP97 interactions in regulating AQP2 translocation in response to vasopressin in LLC-PKAmerican journal of physiology. Renal physiology · 2019Article
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- Lysosomes integrate metabolic-inflammatory cross-talk in primary macrophage inflammasome activation.The Journal of biological chemistry · 2014Article
- Functional diversity and pharmacological profiles of the FKBPs and their complexes with small natural ligands.Cellular and molecular life sciences : CMLS · 2013Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 intervention.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.