Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases
| Autor: | Damien Fraysse, Peter Chiu, Philip N. Collier, Heather Twin, Luca Settimo, Francoise Pierard, Dean Boyall, Shazia Keily, Claire M. Bolton, Christopher John Davis, Guy Brenchley, Adam P. Curnock, Jaclyn Henderson, Adam Tanner, Juan-Miguel Jimenez, Andrew Miller, Stephen Clinton Young |
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| Rok vydání: | 2013 |
| Předmět: |
Pyridines
T cell T-Lymphocytes Pharmacology Lymphocyte Activation Piperazines Autoimmune Diseases Inhibitory Concentration 50 Mice Antigen In vivo Drug Discovery medicine Potency Animals Humans Protein Kinase Inhibitors Protein kinase C Protein Kinase C chemistry.chemical_classification Chemistry Rational design Cell biology Isoenzymes medicine.anatomical_structure Enzyme Lipophilic efficiency Protein Kinase C-theta Drug Design Molecular Medicine Interleukin-2 |
| Zdroj: | Journal of medicinal chemistry. 56(5) |
| ISSN: | 1520-4804 |
| Popis: | Protein kinase C θ (PKCθ) has a central role in T cell activation and survival; however, the dependency of T cell responses to the inhibition of this enzyme appears to be dictated by the nature of the antigen and by the inflammatory environment. Studies in PKCθ-deficient mice have demonstrated that while antiviral responses are PKCθ-independent, T cell responses associated with autoimmune diseases are PKCθ-dependent. Thus, potent and selective inhibition of PKCθ is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKCθ inhibitors, which show exceptional potency in cells and in vivo. By use of a structure based rational design approach, a 1000-fold improvement in potency and 76-fold improvement in selectivity over closely related PKC isoforms such as PKCδ were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE). |
| Databáze: | OpenAIRE |
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