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.
*Department of Biology, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Adam
A
Curnock
*Department of Biology, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Clare
C
Bolton
*Department of Biology, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Peter
P
Chiu
†Department of Biology Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, U.S.A.
Elisabeth
E
Doyle
‡Department of Chemistry, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Damien
D
Fraysse
†Department of Biology Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, U.S.A.
Matthias
M
Hesse
*Department of Biology, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Julie
J
Jones
*Department of Biology, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Peter
P
Weber
‡Department of Chemistry, Vertex Pharmaceuticals, 86-88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
Juan-Miguel
JM
Jimenez
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta