Optimal linker length for small molecule PROTACs that selectively target p38α and p38ß for degradation.
Eur J Med Chem
; 201: 112451, 2020 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-32634680
ABSTRACT
We report the design of hetero-bifunctional small molecules that selectively target p38α and p38ß for degradation. These proteolysis targeted chimeras (PROTACs) are based on an ATP competitive inhibitor of p38α and p38ß, which is linked to thalidomide analogues to recruit the Cereblon E3 ubiquitin ligase complex. Compound synthesis was facilitated by the use of a copper catalyzed "click" reaction. We show that optimization of the linker length and composition is crucial for the degradation-inducing activity of these PROTACs. We provide evidence that these chemical compounds can induce degradation of p38α and p38ß but no other related kinases at nanomolar concentrations in several mammalian cell lines. Accordingly, the PROTACs inhibit stress and cytokine-induced p38α signaling. Our compounds contribute to understanding the development of PROTACs, and provide a useful tool to investigate functions of the p38 MAPK pathway and its involvement in diseases.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Piridonas
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Talidomida
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Benzamidas
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Proteína Quinase 11 Ativada por Mitógeno
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Proteína Quinase 14 Ativada por Mitógeno
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Espanha