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J Med Chem. 2013 Mar 14;56(5):1799-810. doi: 10.1021/jm301465a. Epub 2013 Feb 11.

Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases.

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Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.


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).

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