title: A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.
abstract: Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.
authors.affiliation: Research Department, CIBA-GEIGY Ltd., Basel, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: U
authors.initials: U
authors.lastname: Regenass
authors.forename: D
authors.initials: D
authors.lastname: Fabbro
authors.forename: E
authors.initials: E
authors.lastname: Alteri
authors.forename: J
authors.initials: J
authors.lastname: Rösel
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: G
authors.initials: G
authors.lastname: Caravatti
authors.forename: A
authors.initials: A
authors.lastname: Matter
mesh_terms: D000470:Alkaloids / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001921:Brain / Q000201:enzymology; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000097:blood; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D010764:Phosphorylase Kinase / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D011494:Protein Kinases / Q000302:isolation & purification / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives; D013552:Swine; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D010764:Phosphorylase Kinase; D066246:ErbB Receptors; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin