ATP Site-Directed Inhibitors of Protein Kinase CK2: An Update

Abstract

CK2 denotes a pleiotropic, constitutively active protein kinase whose abnormally high level in many cancer cells is held as an example of "non oncogene addiction". A wide spectrum of cell permeable, fairly specific ATP site-directed CK2 inhibitors are currently available which are proving useful to dissect its biological functions and which share the property of inducing apoptosis of cancer cells with no comparable effect on their "normal" counterparts. One of these, CX-4945, has recently entered clinical trials for the treatment of advanced solid tumors, Castelman's disease and multiple myeloma. The solution of a wide range of 3D structures of inhibitors bound to the catalytic subunits of CK2 reveals that their efficacy substantially relies on hydrophobic interactions within a cavity which is smaller than in other protein kinases. Accordingly the potency of tetra-halogenated benzimidazoles increases upon replacement of chlorine by bromine and, even more, by iodine, and decreases if two unique bulky side chains on CK2 (Val66 and Ile174) are mutated to alanines. Many CK2 inhibitors have been tested on a panel of more than 60 kinases providing Promiscuity Scores useful to evaluate their selectivity, the lowest value (9.47), denoting highest selectivity, being displayed by quinalizarin. The observation that CK2 inhibitors with medium/high promiscuity scores share the ability to inhibit a group of protein kinases as effectively as CK2 discloses the possibility of using their scaffolds for the rational development of selective inhibitors of these kinases, with special reference to PIMs, DYRKs, HIPK2, PKD and ERK8.

Protein Kinase CK2 Protects Multiple Myeloma Cells from ER Stress–Induced Apoptosis and from the Cytotoxic Effect of HSP90 Inhibition through Regulation of the Unfolded Protein Response

“…K27 is a TBB derivative (29) displaying a fairly good specificity for CK2 at the concentration used here. However, as shown in the work of Sarno and colleagues (29), at higher concentrations (10 mmol/L and higher), it is possible that K27 has offtarget effects toward other kinases. Interestingly, Western blot analysis of control and K27-treated U-266 cells revealed significant modifications of the main UPR regulating signaling molecules upon K27: a strong reduction of IRE1a, a reduction of BIP/GRP78 and CHOP/ GADD153 protein levels, and an increase of phosphoSer51 EIF2a levels (Fig.…”

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

“…Most of them are directed toward the ATP binding site, and belong to (i) coumarins (ellagic acid), (ii) polyhalogenated benzimidazoles (TBB), (iii) anthraquinones (emodin), (iv) pyrazolotriazines, (v) indoloquinazolines (IQA) and naphthyridines and related (CX-4945, CX-5011) ( Fig. 1) [11]. Pre-clinically, CX-4945 demonstrated single agent potency in suppressing xenograft tumor growth.…”

The Protein Kinase 2 Inhibitor CX-4945 Regulates Osteoclast and Osteoblast Differentiation In Vitro

“…CK2 is overexpressed in many types of cancer; notably, it affects the proliferation and helps maintain the phenotype of cancer (Ahmed, 1999;Ahmed et al, 2002;Allende and Allende, 1995;Guerra and Issinger, 1999). Recent reviews provide a potent rationale for considering CK2 as a therapeutic target for human cancer, and several CK2 inhibitors have been developed and are being tested in ongoing clinical trials (Cozza et al, 2012;Sarno et al, 2011).…”