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.
Conference Article| October 25 2007
Structure-based optimization of PKCθ inhibitors
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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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