Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling.
Cell Chem Biol
; 27(1): 66-73.e7, 2020 01 16.
Article
em En
| MEDLINE
| ID: mdl-31859249
ABSTRACT
The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over half of tumors exhibiting aberrant AKT activation. Although potent small-molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of the ATP-competitive AKT inhibitor GDC-0068 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 h, even after compound washout. Our findings suggest that AKT degradation may confer prolonged pharmacological effects compared with inhibition, and highlight the potential advantages of AKT-targeted degradation.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Pirimidinas
/
Transdução de Sinais
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Inibidores de Proteínas Quinases
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Proteínas Proto-Oncogênicas c-akt
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Descoberta de Drogas
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Proteólise
Limite:
Humans
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2020
Tipo de documento:
Article