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. Cancer Res; 70(23); 9865-74. Ó2010 AACR.

Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

“…The ellipticine derivative N2-methyl-9-hydroxyellipticium has been used in the treatment of breast cancer, but it has been retrieved because of its toxicity. Previous studies have shown that Pyr1 is a weak DNA intercalator and has no effect on topoisomerase II (26).…”

Design, synthesis and evaluation of 2-phenylisothiazolidin-3-one-1,1-dioxides as a new class of human protein kinase CK2 inhibitors

“…The binding mode of compound 31 predicted by molecular docking is similar to the interactions of compounds 18E and 19E with CK2, three-dimensional structures of these complexes were determined by X-ray crystallography 16 . All three compounds form hydrogen bonds with kinase hinge-region by the oxygen atom, employing carboxylic acid oxygen in the case of compound 31 and oxygen of the phenoxy group in the case of compounds 18E and 19E.…”

Force et spécificité du criblage pour des molécules bioactives au CMBA-Grenoble

“…La mise au point d'un test enzymatique simple et robuste a permis d'identifier des inhibiteurs présentant des propriétés anticancéreuses prometteuses (Tableau I). Ainsi, des dérivés des pyridocarbazoles et des benzopyridoindoles ont été caractérisés comme des inhibiteurs de CK2, agissant comme compétiteurs de l'ATP et présentant des propriétés antiprolifératives dans un modèle de xénogreffe de glioblastome humain [5]. Trois dérivés de REVUES [22].…”

“…Utilisés quotidiennement en laboratoire, les tests et le savoir-faire des chercheurs constituent une ressource largement sous exploitée pour le criblage et la découverte de molécules bioactives. Le champ d'application de ces molécules ne se limite pas au secteur du médicament : les molécules chimiques découvertes au centre de criblage pour des molécules bioactives du CEA-Grenoble (CMBA-Grenoble) se révèlent des outils prometteurs tant en recherche fondamentale [3][4][5][6][7][8][9] que pour des applications dans les domaines de la santé 2 , de l'environnement ou des bioénergies 3 .…”