Inhibition of protein kinase CK2 by condensed polyphenolic derivatives. An in vitro and in vivo study.
ATP site-directed inhibitors that can target individual kinases are powerful tools for use in signal transduction research, all the more so in the case of a pleiotropic, constitutively active protein kinase such as CK2, which is not turned on in response to specific stimuli. By screening a library of more than 200 derivatives of natural polyphenolic compounds, we have identified 16 molecules which inhibit CK2 with IC(50) values of <or=1 microM. They belong to the classes of anthraquinones (six compounds), xanthenones (two compounds), fluorenones (one compound), and coumarins (seven compounds), and their inhibitory potency correlates with the presence of nitro, amino, or halogen substituents at specific positions. Three of the most potent inhibitors, MNX (1,8-dihydroxy-4-nitroxanthen-9-one), NBC (8-hydroxy-4-methyl-9-nitrobenzo[g]chromen-2-one), and DBC (3,8-dibromo-7-hydroxy-4-methylchromen-2-one), whose IC(50) values range between 0.13 and 0.36 microM, are quite specific toward CK2 within a panel of 33 protein kinases tested. Treatment of Jurkat cells with these compounds promotes inhibition of endogenous CK2 and induction of apoptosis. A correlation is observed between their efficacy as CK2 inhibitors (as judged from IC(50) values) and their capacity to induce cell death (DC(50) values). Mutations of the unique CK2alpha residues Val66 and/or Ile174 to alanine have a detrimental effect on inhibition by these compounds with 16-67-fold increases in IC(50) values. The combined usage of these reagents can be exploited to gain information about cellular functions mediated by CK2.
Dipartimento di Chimica Biologica, Istituto di Neuroscienze del CNR, Università di Padova, Padova, Italy.
Flavio
F
Meggio
Mario A
MA
Pagano
Stefano
S
Moro
Giuseppe
G
Zagotto
Maria
M
Ruzzene
Stefania
S
Sarno
Giorgio
G
Cozza
Jenny
J
Bain
Matthew
M
Elliott
Arianna Donella
AD
Deana
Anna Maria
AM
Brunati
Lorenzo A
LA
Pinna
D017209:Apoptosis / Q000187:drug effects; D047390:Casein Kinase II; D002463:Cell Membrane Permeability / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D005419:Flavonoids; D010636:Phenols; D059808:Polyphenols; D047390:Casein Kinase II; D017346:Protein Serine-Threonine Kinases