Chelerythrine is a potent and specific inhibitor of protein kinase C.
The benzophenanthridine alkaloid chelerythrine is a potent, selective antagonist of the Ca++/phospholopid-dependent protein kinase (Protein kinase C: PKC) from the rat brain. Half-maximal inhibition of the kinase occurs at 0.66 microM. Chelerythrine interacted with the catalytic domain of PKC, was a competitive inhibitor with respect to the phosphate acceptor (histone IIIS) (Ki = 0.7 microM) and a non-competitive inhibitor with respect to ATP. This effect was further evidenced by the fact that chelerythrine inhibited native PKC and its catalytic fragment identically and did not affect [3H]- phorbol 12,13 dibutyrate binding to PKC. Chelerythrine selectively inhibited PKC compared to tyrosine protein kinase, cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase. The potent antitumoral activity of celerythrine measured in vitro might be due at least in part to inhibition of PKC and thus suggests that PKC may be a model for rational design of antitumor drugs.
Herbert
J M
JM
Sanofi Recherche, Toulouse, France.
Augereau
J M
JM
Gleye
J
J
Maffrand
J P
JP
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D053119:Benzophenanthridines; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002471:Cell Transformation, Neoplastic; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000201:enzymology; D010617:Phenanthridines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D019311:Staurosporine; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D053119:Benzophenanthridines; D007546:Isoquinolines; D010617:Phenanthridines; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C016299:chelerythrine; D011493:Protein Kinase C; D019311:Staurosporine