Selective protein kinase Cθ (PKCθ) inhibitors for the treatment of autoimmune diseases

Protein kinase C theta (PKC theta) is a member of a large family of serine/threonine kinases that are involved in diverse cellular functions. PKC theta has roles in T-cell activation and survival, where the dependency of T-cell responses on this enzyme appears to be dictated by both the nature of the antigen and by the inflammatory environment. Studies in PKC theta-deficientmice have demonstrated that although anti-viral responses are PKC theta-independent, T-cell responses associated with autoimmune diseases are PKC theta-dependent. PKC theta-deficient mice are either resistant to or show markedly reduced symptoms in models of MS (multiple sclerosis), IBD (inflammatory bowel disease), arthritis and asthma. Thus potent and selective inhibition of PKC theta has the potential to block T-cell-mediated autoimmunity without compromising anti-viral responses. The present review describes the design and optimization of potent and selective PKC theta inhibitors and their efficacy in both in vitro and in vivo studies. First, our compounds confirm the critical role for PKC theta in T-cell activation and proliferation and secondly they help to demonstrate that murine and human memory T-cell function continues to be dependent on this enzyme. In addition, these inhibitors demonstrate impressive efficacy in treating established autoimmune disease in murine models of IBD and MS.