Document Report Card

ID: ALA1126671

Journal: J Med Chem

Title: Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restriction.

Authors: Bit RA, Davis PD, Elliott LH, Harris W, Hill CH, Keech E, Kumar H, Lawton G, Maw A, Nixon JS.

Abstract: The protein kinase inhibitor staurosporine has been used to design a series of selective bisindolylmaleimide inhibitors of protein kinase C (PKC). Guided by molecular graphics, conformational restriction of the cationic side chain has led to ATP competitive inhibitors of improved potency and selectivity. Two compounds have been further evaluated and were shown to inhibit PKC of human origin and prevent T-cell activation in a human allogeneic mixed lymphocyte reaction. One of these compounds was orally absorbed in mice and antagonized a phorbol ester induced paw edema in a dose-dependent manner. This compound also selectively inhibited the secondary T-cell mediated response in a developing adjuvant arthritis model in rats and provides evidence for the potential use of PKC inhibitors as therapeutic immunomodulators.

CiteXplore: 8421286

DOI: 10.1021/jm00053a003