Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2.

Abstract	The alkyloid compound ellipticine derived from the berrywood tree is a topoisomerase II poison that is used in ovarian and breast cancer treatment. In this study, we report the identification of ellipticine derivatives and their tetracyclic angular benzopyridoindole analogues as novel ATP-competitive inhibitors of the protein kinase CK2. In vitro and in vivo assays showed that these compounds have a good pharmacologic profile, causing a marked inhibition of CK2 activity associated with cell cycle arrest and apoptosis in human cancer cells. Further, in vivo assays demonstrate antitumor activity in a mouse xenograft model of human glioblastoma. Finally, crystal structures of CK2-inhibitor complex provide structural insights on the molecular basis of CK2 inhibition. Our work lays the foundation for development of clinically useful CK2 inhibitors derived from a well-studied scaffold with suitable pharmacokinetics parameters.
Authors	Renaud Prudent, Virginie Moucadel, Chi-Hung Nguyen, Caroline Barette, Frédéric Schmidt, Jean-Claude Florent, Laurence Lafanechère, Céline F Sautel, Eve Duchemin-Pelletier, Elodie Spreux, Odile Filhol, Jean-Baptiste Reiser, Claude Cochet
Journal	Cancer research (Cancer Res) Vol. 70 Issue 23 Pg. 9865-74 (Dec 01 2010) ISSN: 1538-7445 [Electronic] United States
PMID	21118972 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Carbazoles Ellipticines Indoles carbazole ellipticine Casein Kinase II
Topics	Amino Acid Sequence Animals Antineoplastic Agents (chemistry, pharmacology) Apoptosis (drug effects) Blotting, Western Carbazoles (chemistry, pharmacology) Casein Kinase II (antagonists & inhibitors, chemistry, metabolism) Cell Cycle (drug effects) Cell Line Cell Line, Tumor Cell Survival (drug effects) Crystallography, X-Ray Ellipticines (chemistry, pharmacology) Female HeLa Cells Humans Indoles (chemistry, pharmacology) Kinetics Mice Mice, Nude Molecular Structure Neoplasms (drug therapy, enzymology, pathology) Tumor Burden (drug effects) Xenograft Model Antitumor Assays

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