INHIBITORS OF PROTEIN-KINASE-C .2. SUBSTITUTED BISINDOLYMALEIMIDES WITH IMPROVED POTENCY AND SELECTIVITY

A hypothetical mode of inhibition of protein kinase C (PKC) by the nat ural product staurosporine has been used as a basis for the design of substituted bisindolylmaleimides with improved potency over the parent compound. Structure-activity relationships were consistent with the i nteraction of a cationic group in the inhibitor with a carboxylate gro up in the enzyme, and the most potent compound had a K(i) of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent pro tein kinase (PKA) only at much higher concentrations despite the exten sive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human a llogeneic mixed lymphocyte reaction pointing to the potential utility of PKC inhibitors in immunosuppressive therapy. One of these compounds was orally absorbed in the rat and represents an attractive lead in t he development of PKC inhibitors as drugs.