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

Protein kinase Cθ (PKCθ) is a member of a large family of serine/threonine kinases that are involved in diverse cellular functions. PKCθ 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 PKCθ-deficient mice have demonstrated that although anti-viral responses are PKCθ-independent, T-cell responses associated with autoimmune diseases are PKCθ-dependent. PKCθ-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 PKCθ 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 PKCθ inhibitors and their efficacy in both in vitro and in vivo studies. First, our compounds confirm the critical role for PKCθ 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.

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

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).

Structure-based optimization of aminopyridines as PKCθ inhibitors.

The identification of a novel series of PKCθ inhibitors and subsequent optimization using docking based on a crystal structure of PKCθ is described. SAR was rapidly generated around an amino pyridine-ketone hit; (6-aminopyridin-2-yl)(2-aminopyridin-3-yl)methanone 2 leading to compound 21 which significantly inhibits production of IL-2 in a mouse SEB-IL2 model.

The discovery of the potent aurora inhibitor MK-0457 (VX-680).

The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.