Journal
CANCER RESEARCH
Volume 70, Issue 23, Pages 9865-9874Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-0917
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Funding
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National pour la Recherche Scientifique (CNRS)
- Commissariat a l'Energie atomique (CEA)
- Institut Curie
- Ligue Nationale Contre le Cancer
- Institut National du Cancer [57]
- Fondation pour la Recherche Medicale
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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. (C)2010 AACR.
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