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.