Molecular Plasticity of Crystalline CK2α' Leads to KN2, a Bivalent Inhibitor of Protein Kinase CK2 with Extraordinary Selectivity.
J Med Chem
; 65(2): 1302-1312, 2022 01 27.
Article
em En
| MEDLINE
| ID: mdl-34323071
ABSTRACT
CK2α and CK2α' are paralogous catalytic subunits of CK2, which belongs to the eukaryotic protein kinases. CK2 promotes tumorigenesis and the spread of pathogenic viruses like SARS-CoV-2 and is thus an attractive drug target. Efforts to develop selective CK2 inhibitors binding offside the ATP site had disclosed the αD pocket in CK2α; its occupation requires large conformational adaptations of the helix αD. As shown here, the αD pocket is accessible also in CK2α', where the necessary structural plasticity can be triggered with suitable ligands even in the crystalline state. A CK2α' structure with an ATP site and an αD pocket ligand guided the design of the bivalent CK2 inhibitor KN2. It binds to CK2 with low nanomolar affinity, is cell-permeable, and suppresses the intracellular phosphorylation of typical CK2 substrates. Kinase profiling revealed a high selectivity of KN2 for CK2 and emphasizes the selectivity-promoting potential of the αD pocket.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Caseína Quinase II
/
Inibidores de Proteínas Quinases
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Alemanha