Structure-based optimization of PKCθ inhibitors

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. Abbreviations: IL-2, interleukin-2; MAPK, mitogen-activated protein kinase; PDK1, 3-phosphoinositide-dependent protein kinase-1; PKA, protein kinase A; PKC, protein kinase C; P-loop, glycine-rich loop; p[NH]ppA, adenosine 5′-[β,γ-imido]triphosphate; SAR, structure–activity relationship; TCR, T-cell receptor