Chemically induced degradation of CK2 by proteolysis targeting chimeras based on a ubiquitin-proteasome pathway.
Bioorg Chem
; 81: 536-544, 2018 12.
Article
em En
| MEDLINE
| ID: mdl-30245235
ABSTRACT
As a ubiquitous, highly pleiotropic and constitutively active serine/threonine protein kinase, casein kinase 2 (CK2) is closely associated with tumorigenesis by its overexpression in cancer cells. Here we report several proteolysis targeting chimeras (PROTACs) via "click reaction" to connect a CK2 inhibitor (CX-4945) and pomalidomide for degradation of CK2 protein. Among them, compound 2 degraded CK2 in a dose and time-dependent manner, and kept CK2 at a low basal level by recruiting ubiquitin-proteasome system. The degradation of CK2 resulted in the reduced phosphorylation of Akt and the up-regulation of p53. As a CK2 protein degrader, 2 showed the analogous cytotoxicity to CX-4945 but with a quite different mechanism of action from the CK2 inhibitor, hinting that degradation of CK2 proteins by PROTACs is a potential way for cancer treatments.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Apoptose
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Caseína Quinase II
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Proteólise
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article