Tetrabromocinnamic acid (TBCA) and related compounds represent a new class of specific protein kinase CK2 inhibitors.
Abnormally high constitutive activity of protein kinase CK2, levels of which are elevated in a variety of tumours, is suspected to underlie its pathogenic potential. The most widely employed CK2 inhibitor is 4,5,6,7-tetrabromobenzotriazole (TBB), which exhibits a comparable efficacy toward another kinase, DYRK1 a. Here we describe the development of a new class of CK2 inhibitors, conceptually derived from TBB, which have lost their potency toward DYRK1 a. In particular, tetrabromocinnamic acid (TBCA) inhibits CK2 five times more efficiently than TBB (IC50 values 0.11 and 0.56 microM, respectively), without having any comparable effect on DYRK1 a (IC50 24.5 microM) or on a panel of 28 protein kinases. The usefulness of TBCA for cellular studies has been validated by showing that it reduces the viability of Jurkat cells more efficiently than TBB through enhancement of apoptosis. Collectively taken, the reported data support the view that suitably derivatized tetrabromobenzene molecules may provide powerful reagents for dissecting the cellular functions of CK2 and counteracting its pathogenic potentials.
Pagano
Mario A
MA
Department of Biological Chemistry and CNR Institute of Neurosciences, University of Padova viale G. Colombo 3, 35121 Padova, Italy.
Poletto
Giorgia
G
Di Maira
Giovanni
G
Cozza
Giorgio
G
Ruzzene
Maria
M
Sarno
Stefania
S
Bain
Jenny
J
Elliott
Matthew
M
Moro
Stefano
S
Zagotto
Giuseppe
G
Meggio
Flavio
F
Pinna
Lorenzo A
LA
D000255:Adenosine Triphosphate / Q000737:chemistry; D017209:Apoptosis; D001665:Binding Sites; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002934:Cinnamates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation
D002934:Cinnamates; D004791:Enzyme Inhibitors; C518786:tetrabromocinnamic acid; C029010:cinnamic acid; D000255:Adenosine Triphosphate; D047390:Casein Kinase II