期刊
SCIENTIFIC REPORTS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-019-52141-5
关键词
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资金
- NIH/NIGMS R01 grant [GM074832]
- NIH R01 grants [AI118985, GM117424]
- Institut National de la Sante et de la Recherche Medicale (Inserm)
- Commissariat a l'energie Atomique a l'Energie Atomique et aux Energies Alternatives (CEA)
- Ligue Nationale contre le Cancer
- Institut National du Cancer [57]
- Agence Nationale de la Recherche [PCV08_324733]
- Universite Grenoble-Alpes (UGA)
- Region Rhone-Alpes (grant ARC 1 Sante) [12-008707-01]
- Institut National du Cancer (INCa) [2011-097]
- Ministere de l'Education Nationale de la Recherche et de Technologie (MENRT)
- Ecole Doctorale Interdisciplinaire Sciences-Sante (EDISS)
- GRAL within University Grenoble Alpes graduate school (Ecoles Universitaires de Recherche) CBH-EUR-GS [ANR-17-EURE-0003]
CK2 is a constitutively active protein kinase overexpressed in numerous malignancies. Interaction between CK2 alpha and CK2 beta subunits is essential for substrate selectivity. The CK2 alpha/CK2 beta 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 CK2 alpha/CK2 beta 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 CK2 alpha 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.
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