Quinalizarin as a potent, selective and cell permeable inhibitor of protein kinase CK2

Overview & Synopsis

Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a moderately potent and poorly selective inhibitor of CK2, one of the most pleiotropic Ser/Thr protein kinases, implicated in neoplasia and in other global diseases. By virtual screening of the MMS database we have now identified quinalizarin (1,2,5,8-tetrahydroxy-anthraquinone) as an inhibitor of CK2 more potent and selective than emodin. CK2 inhibition by quinalizarin is competitive with respect to ATP, with a Ki value around 50 nM. Tested at 1 μM concentration on a panel of 75 protein kinases, quinalizarin drastically inhibits only CK2, with a promiscuity score (11.1) which is the lowest ever reported so far for a CK2 inhibitor. Especially remarkable is the ability of quinalizarin to discriminate between CK2 and a number of kinases, notably DYRK1a, PIMs 1, 2 and 3, HIPK2, MNK1, ERK8 and PKD1, which conversely tend to be inhibited as drastically as CK2 by commercially available CK2 inhibitors. The determination of the crystal structure of a complex between quinalizarin and CK2alpha subunit highlights the relevance of polar interactions in stabilizing the binding, an unusual characteristic for a CK2 inhibitor, and disclose other structural features which may account for the narrow selectivity of this compound. Tested on Jurkat cells, quinalizarin proved able to inhibit endogenous CK2 and to induce apoptosis more efficiently than the commonly used CK2 inhibitors TBB and DMAT.