Small Molecule Inhibitors of PKCθ as Potential Antiinflammatory Therapeutics

Members of the protein kinase C (PKC) family of serine/threonine kinases have been targeted for drug discovery for over 20 years, initially focusing on inhibitors of the classic PKCs, which include the alpha,beta, and gamma isoforms. Recently, inhibition of the activity of the novel PKC isoforms, namely theta,delta,epsilon, and eta, has become a focus of research. PKC theta, first identified in 1992, is a key enzyme in the regulation of T cell activation and survival. While T cells play critical roles in initiating and controlling the immune response, inappropriate or extended stimulation of T cells is responsible for many chronic inflammatory diseases. Mice with an engineered deficiency in PKC theta have reduced incidence and severity of several inflammatory disorders including asthma, arthritis, inflammatory bowel disease, multiple sclerosis, and allograft rejection. This review summarizes the efforts directed towards the design of small molecule PKC theta inhibitors as potential therapeutic agents.