Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent

CGP 41251 was originally identified as an inhibitor of protein kinase C (PK C), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase i nsert domain-containing receptor; which is involved in angiogenesis. CGP 41 251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induce d by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptor s for platelet-derived growth factor, stem cell factor, and VEGF (kinase in sert domain-containing receptor) that correlated with the inhibition of the mitogen activated protein kinase activation, but did not affect the ligand induced autophosphorylation of the receptors for insulin, insulin-like gro wth factor I, or epidermal growth factor. CGP 41251 showed broad antiprolif erative activity against Various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumo r cells in vitro. CGP 41251 showed in vivo antitumor activity as single age nt and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor g rowth by inhibiting tumor angiogenesis (via its effects on the VEGF recepto r tyrosine kinases) in addition to directly inhibiting tumor cell prolifera tion (via its effects on PKCs). (C) 1999 Elsevier Science Inc. All rights r eserved.