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.
Highlights
Protein kinases represent major therapeutic targets and several kinase inhibitors have demonstrated powerful clinical activity in pathologies in which the target kinase is dysregulated.Protein kinase CK2 plays critical roles in cell growth, cell differentiation, apoptosis, and oncogenic transformation [1, 2]
CK2 has been found dysregulated in many cancers and its dual function in promotion of cell growth and in suppression of apoptosis may be relevant to its oncogenic potential [3]
Cell culture HeLa, U373, MCF-10A, MESSA, and MESSA Dx5 cell lines were obtained from the American Type Culture Collection (ATCC) during 2005
Summary
Protein kinases represent major therapeutic targets and several kinase inhibitors have demonstrated powerful clinical activity in pathologies in which the target kinase is dysregulated. Protein kinase CK2 plays critical roles in cell growth, cell differentiation, apoptosis, and oncogenic transformation [1, 2]. CK2 has been found dysregulated in many cancers and its dual function in promotion of cell growth and in suppression of apoptosis may be relevant to its oncogenic potential [3]. The recent association of aberrant CK2 expression with unfavorable prognostic markers in prostate cancer [4] and in acute myeloid leukemia [5] supports the direct implication of CK2 in tumor formation and recurrence. CK2 is considered as a promising therapeutic target, supporting the development of chemical inhibitors.
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