Unprecedented Selectivity and Structural Determinants of a New Class of Protein Kinase CK2 Inhibitors in Clinical Trials for the Treatment of Cancer

Abstract

5-(3-Chlorophenylamino)benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first clinical stage inhibitor of protein kinase CK2 for the treatment of cancer, is representative of a new class of CK2 inhibitors with K(i) values in the low nanomolar range and unprecedented selectivity versus other kinases. Here we present the crystal structure of the complexes of CX-4945 and two analogues (CX-5011 and CX-5279) with the catalytic subunit of human CK2. Consistent with their ATP-competitive mode of inhibition, all three compounds bind in the active site of CK2 (type I inhibitors). The tricyclic scaffold of the inhibitors superposes on the adenine of ATP, establishing multiple hydrophobic interactions with the binding cavity. The more extended scaffold, as compared to that of ATP, allows the carboxylic function, shared by all three ligands, to penetrate into the deepest part of the active site where it makes interactions with conserved water W1 and Lys-68, thus accounting for the crucial role of this negatively charged group in conferring high potency to this class of inhibitors. The presence of a pyrimidine in CX-5011 and in CX-5279 instead of a pyridine (as in CX-4945) ring is likely to account for the higher specificity of these compounds whose Gini coefficients, calculated by profiling them against panels of 102 and/or 235 kinases, are significantly higher than that of CX-4945 (0.735 and 0.755, respectively, vs 0.615), marking the highest selectivity ever reported for CK2 inhibitors.

Phosphoproteomics of MAPK Inhibition in BRAF-Mutated Cells and a Role for the Lethal Synergism of Dual BRAF and CK2 Inhibition

“…We treated cells with a relatively new and specific inhibitor of CK2 (CX-4945; ref. 43) alone and in combination with vemurafenib or selumetinib. Growth inhibition was additive when combined with vemurafenib, increasing cell death by 15% to 25% in both thyroid and melanoma cell lines harboring the BRAFV600E mutation.…”

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

“…The crystal structure of the CK2/ CX-4945 complex (pdb: 3pe1) [48] was used as starting structure for the MD simulations; having removed the sulfate ions and water molecules, except those water molecules located within 5 A of the ligand. The CK2/1f complex was built in silico by superposing the central ring atoms of the ligand with the corresponding atoms of the CX-4945 compound in the CK2/CX-4945 complex.…”

Gene Expression and Regulation in Mammalian Cells - Transcription From General Aspects

“…CK2 has additionally been shown to potentiate aberrant activation of oncoproteins including NF-κB [56], and AKT [67]. Drugs that inhibit CK2 have proven to be well-tolerated in a number of clinical trials and systemic or local delivery of these inhibitors is therefore a potential treatment for multiple disease states [68,69].…”