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Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity.

Basic Information

ID: ALA1126323

Journal: J Med Chem

Title: Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity.

Authors: Davis PD, Elliott LH, Harris W, Hill CH, Hurst SA, Keech E, Kumar MK, Lawton G, Nixon JS, Wilkinson SE.

Abstract: A hypothetical mode of inhibition of protein kinase C (PKC) by the natural 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 interaction of a cationic group in the inhibitor with a carboxylate group in the enzyme, and the most potent compound had a Ki of 3 nM. The inhibitors were competitive with ATP but inhibited cAMP-dependent protein kinase (PKA) only at much higher concentrations despite the extensive sequence homology between the ATP-binding regions of PKA and PKC. Three compounds were evaluated further and found to inhibit a human allogeneic 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 the development of PKC inhibitors as drugs.

CiteXplore: 1552513

DOI: 10.1021/jm00084a004

Patent ID: