Ribofuranosyl‐benzimidazole derivatives as inhibitors of casein kinase‐2 and casein kinase‐1

Open Access
Publisher Website
Google Scholar
Abstract
5,6‐Dichloro‐1‐(β‐d‐ribofuranosyl)benzimidazole (DiCl‐RB) is a powerful inhibitor of casein kinase‐2 (CK‐2) [Zandomeni, R. et al. (1986) J. Biol. Chem. 261, 3414–3420]. Here a series of 17 analogues of DiCl‐RB has been employed for studying the specificity and the mode of action of this family of CK‐2 inhibitors. The two halogen substituents on the benzene ring are shown to play a prominent role in inhibition, the 5,6‐dibromo derivative (DiBr‐RB) being fivefold more effective than DiCl‐RB (Ki= 2 μ M cf. 10 μ M, with GTP as substrate), whereas the difluoro derivative (DiF‐RB) is nearly as ineffective as unsubstituted 1‐(β‐d‐ribofuranosyl)benzimidazole. On the other hand, although some modifications of the ribose group significantly decrease the inhibitory efficiency, the sugar moiety is not strictly required, since dichlorobenzimidazole itself (DiCl‐Bz) is an inhibitor almost as good as DiCl‐RB. Inhibition of CK‐2 by DiCl‐RB and by its analogues, DiCl‐Bz included, is of the competitive type with respect to the nucleotide substrate, the Ki values being lower with GTP than with ATP. The Ki values of the most potent inhibitor, DiBr‐RB, with ATP and GTP, are 6 μ M and 2 μ M, respectively, denoting an affinity for the enzyme higher than that of the physiological substrates, ATP and GTP. DiBr‐RB has been assayed for its inhibitory capacity toward several protein kinase other than CK‐2. Protein kinase‐C, cAMP‐dependent protein kinase, the Ser/Thr protein kinase expressed by Pseudorabies virus, and four different tyrosine protein kinases from spleen, proved insensitive to DiBr‐RB concentrations capable of almost entirely suppressing the activity of rat liver and maize seedling CK‐2. Casein kinase‐1 however is nearly as sensitive as CK‐2 to DiBr‐RB. Inhibition of CK‐1 is also of the competitive type with respect to ATP (Ki= 14 μ M). Although the inhibitory spectrum of CK‐1 by the various analogues is reminiscent of that observed with CK‐2, a remarkable difference is revealed by 5′‐phosphorylation of ribose which increases the Ki with CK‐2 while decreasing that with CK‐1.