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

Protein kinase C theta (PKC theta) 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 PKC theta-deficient mice have demonstrated that while antiviral responses are PKC theta-independent, T cell responses associated with autoimmune diseases are PKC theta-dependent. Thus, potent and selective inhibition of PKC theta is expected to block autoimmune T cell responses without compromising antiviral immunity. Herein, we describe the development of potent and selective PKC theta 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 PKC delta were obtained from the initial HTS hit, together with a big improvement in lipophilic efficiency (LiPE).