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).
