title: 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.
authors.affiliation: Venetian Institute of Molecular Medicine, Via G. Orus 2, 35129 Padova, Italy. roberto.battistutta@unipd.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Battistutta
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cozza
authors.forename: Fabrice
authors.initials: F
authors.lastname: Pierre
authors.forename: Elena
authors.initials: E
authors.lastname: Papinutto
authors.forename: Graziano
authors.initials: G
authors.lastname: Lolli
authors.forename: Stefania
authors.initials: S
authors.lastname: Sarno
authors.forename: Sean E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: Adam
authors.initials: A
authors.lastname: Siddiqui-Jain
authors.forename: Mustapha
authors.initials: M
authors.lastname: Haddach
authors.forename: Kenna
authors.initials: K
authors.lastname: Anderes
authors.forename: David M
authors.initials: DM
authors.lastname: Ryckman
authors.forename: Flavio
authors.initials: F
authors.lastname: Meggio
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
mesh_terms: D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy; D010619:Phenazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C568366:3-(cyclopropylamino)-5-(3-(trifluoromethyl)phenylamino)pyrimido(4,5-c)quinoline-8-carboxylic acid; C568365:5-(3-ethynylphenylamino)pyrimido(4,5-c)quinoline-8-carboxylic acid; D009287:Naphthyridines; D010619:Phenazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C555142:silmitasertib; D047390:Casein Kinase II