Antitumor activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase CK2.
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.
INSERM, U873, Grenoble, France.
Renaud
R
Prudent
Virginie
V
Moucadel
Chi-Hung
CH
Nguyen
Caroline
C
Barette
Frédéric
F
Schmidt
Jean-Claude
JC
Florent
Laurence
L
Lafanechère
Céline F
CF
Sautel
Eve
E
Duchemin-Pelletier
Elodie
E
Spreux
Odile
O
Filhol
Jean-Baptiste
JB
Reiser
Claude
C
Cochet
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002227:Carbazoles; D004611:Ellipticines; D007211:Indoles; C041514:carbazole; C034192:ellipticine; D047390:Casein Kinase II