S.E. Wilkinson* and J.S. Nixon Pages 596 - 609 ( 14 )
The protein kinase C ( PKC) family of isoenzymes was thought to mediate a wide range of signal transduction processes in cells. However, it is now widely accepted that its role may have been overstated. The advent of selective PKC inhibitors has led to a re-appraisal of the role this enzyme plays in these processes. This review shows how the structural lead provided by staurosporine, a non-selective protein kinase inhibitor, was used as a basis for the design of substituted bisindolylmaleimides with significantly improved selectivity for protein kinase C over cAMP-dependent protein kinase and phophorylase kinase. Evidence from studies with these inhibitors implicates PKC in inflammatory responses such as the neutrophil respiratory burst and antigen-driven T cell proliferation. Potent, orally bioavailable bisindolylmaleimide PKC inhibitors such as Ro 32-0432 inhibit phorbol ester -induced inflammation in rodents. These agents also selectively inhibit T cell mediated responses in animal models of arthritis and encephalomyelitis. Taken together, these results suggest that selective inhibitors of PKC may be useful in the therapy of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and psoriasis.