title: Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent.
abstract: CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced 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 receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert 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 growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).
authors.affiliation: Department of Oncology, Novartis Pharma Inc., Basel, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Fabbro
authors.forename: E
authors.initials: E
authors.lastname: Buchdunger
authors.forename: J
authors.initials: J
authors.lastname: Wood
authors.forename: J
authors.initials: J
authors.lastname: Mestan
authors.forename: F
authors.initials: F
authors.lastname: Hofmann
authors.forename: S
authors.initials: S
authors.lastname: Ferrari
authors.forename: H
authors.initials: H
authors.lastname: Mett
authors.forename: T
authors.initials: T
authors.lastname: O'Reilly
authors.forename: T
authors.initials: T
authors.lastname: Meyer
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000502:physiology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005544:Forecasting; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000145:classification; D017978:Receptors, Growth Factor / Q000187:drug effects*; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D017978:Receptors, Growth Factor; D011494:Protein Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019311:Staurosporine; C059539:midostaurin