PKCθ (protein kinase Cθ) is a central signalling molecule in the T-cell receptor activation pathway and is a target for treatment of a number of diseases. Several PKC inhibitors are in the drug-discovery pharmaceutical programmes today for the treatment of cancer, diabetes and arthritis. CD4+ T-lymphocytes also play a critical role in the initiation and progression of allergic airway inflammation. Our goal is the development of PKCθ antagonists as a means to control asthma and autoimmune diseases, using the strategy based on developing small-molecule agents that would block the enzyme's catalytic activity. Here, we discuss our work on the discovery of lead chemical series and review our X-ray structural and modelling approaches, including a structure-surrogate strategy that helped guide us in the lead compound optimizations.
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November 2007
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Conference Article|
October 25 2007
Structure-based optimization of PKCθ inhibitors
L. Mosyak;
*Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, U.S.A.
2Correspondence may be addressed to either of these authors (email dchaudhary@wyeth.com or lmosyak@wyeth.com).
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Z. Xu;
Z. Xu
*Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, U.S.A.
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D. Joseph-McCarthy;
D. Joseph-McCarthy
*Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, U.S.A.
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N. Brooijmans;
N. Brooijmans
*Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, U.S.A.
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W. Somers;
W. Somers
*Chemical and Screening Sciences, Wyeth Research, Cambridge, MA 02140, U.S.A.
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D. Chaudhary
†Inflammation, Wyeth Research, Cambridge, MA 02140, U.S.A.
2Correspondence may be addressed to either of these authors (email dchaudhary@wyeth.com or lmosyak@wyeth.com).
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Publisher: Portland Press Ltd
Received:
June 19 2007
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem Soc Trans (2007) 35 (5): 1027–1031.
Article history
Received:
June 19 2007
Citation
L. Mosyak, Z. Xu, D. Joseph-McCarthy, N. Brooijmans, W. Somers, D. Chaudhary; Structure-based optimization of PKCθ inhibitors. Biochem Soc Trans 1 November 2007; 35 (5): 1027–1031. doi: https://doi.org/10.1042/BST0351027
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