1321924-70-2Relevant articles and documents
Design and optimization of selective protein kinase C θ (PKCθ) inhibitors for the treatment of autoimmune diseases
Jimenez, Juan-Miguel,Boyall, Dean,Brenchley, Guy,Collier, Philip N.,Davis, Christopher J.,Fraysse, Damien,Keily, Shazia B.,Henderson, Jaclyn,Miller, Andrew,Pierard, Francoise,Settimo, Luca,Twin, Heather C.,Bolton, Claire M.,Curnock, Adam P.,Chiu, Peter,Tanner, Adam J.,Young, Stephen
, p. 1799 - 1810 (2013/04/24)
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).
PYRAZOLOPYRIDINE KINASE INHIBITORS
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, (2011/08/21)
The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, co
