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.
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December 2014
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Conference Article|
November 17 2014
Selective protein kinase Cθ (PKCθ) inhibitors for the treatment of autoimmune diseases
Adam Curnock;
Adam Curnock
*Department of Biology, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
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Clare Bolton;
Clare Bolton
*Department of Biology, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
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Peter Chiu;
Peter Chiu
*Department of Biology, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
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Elisabeth Doyle;
Elisabeth Doyle
†Department of Biology Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, U.S.A.
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Damien Fraysse;
Damien Fraysse
‡Department of Chemistry, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
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Matthias Hesse;
Matthias Hesse
†Department of Biology Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, U.S.A.
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Julie Jones;
Julie Jones
*Department of Biology, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
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Peter Weber;
Peter Weber
*Department of Biology, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
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Juan-Miguel Jimenez
Juan-Miguel Jimenez
1
‡Department of Chemistry, Vertex Pharmaceuticals, 86–88 Jubilee Avenue, Milton Park, Abingdon, Oxfordshire OX14 4RW, U.K.
1To whom correspondence should be addressed (emailjuan-miguel_jimenez@vrtx.com).
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Publisher: Portland Press Ltd
Received:
June 06 2014
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem Soc Trans (2014) 42 (6): 1524–1528.
Article history
Received:
June 06 2014
Citation
Adam Curnock, Clare Bolton, Peter Chiu, Elisabeth Doyle, Damien Fraysse, Matthias Hesse, Julie Jones, Peter Weber, Juan-Miguel Jimenez; Selective protein kinase Cθ (PKCθ) inhibitors for the treatment of autoimmune diseases. Biochem Soc Trans 1 December 2014; 42 (6): 1524–1528. doi: https://doi.org/10.1042/BST20140167
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