Discovery of holoenzyme-disrupting chemicals as substrate-selective CK2 inhibitors.
Sci Rep
; 9(1): 15893, 2019 11 04.
Article
de En
| MEDLINE
| ID: mdl-31685885
ABSTRACT
CK2 is a constitutively active protein kinase overexpressed in numerous malignancies. Interaction between CK2α and CK2ß subunits is essential for substrate selectivity. The CK2α/CK2ß interface has been previously targeted by peptides to achieve functional effects; however, no small molecules modulators were identified due to pocket flexibility and open shape. Here we generated numerous plausible conformations of the interface using the fumigation modeling protocol, and virtually screened a compound library to discover compound 1 that suppressed CK2α/CK2ß interaction in vitro and inhibited CK2 in a substrate-selective manner. Orthogonal SPR, crystallography, and NMR experiments demonstrated that 4 and 6, improved analogs of 1, bind to CK2α as predicted. Both inhibitors alter CK2 activity in cells through inhibition of CK2 holoenzyme formation. Treatment with 6 suppressed MDA-MB231 triple negative breast cancer cell growth and induced apoptosis. Altogether, our findings exemplify an innovative computational-experimental approach and identify novel non-peptidic inhibitors of CK2 subunit interface disclosing substrate-selective functional effects.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Holoenzymes
/
Casein Kinase II
/
Inhibiteurs de protéines kinases
Type d'étude:
Guideline
/
Prognostic_studies
Limites:
Humans
Langue:
En
Journal:
Sci Rep
Année:
2019
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique