Biochemistry, 2004, 43, 12931-12936.
Meggio, F., Pagano, M.A., Moro, S., Zagotto, G., Ruzzene, M., Sarno, S.,
Cozza, G., Bain, J., Elliott, M., Donella Deana, A., Brunati, A.M.,
and Pinna, L.A.
Dipartimento di Chimica Biologica, Istituto di
Neuroscienze del CNR, Universita di Padova, Padova, Italy.
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.
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