Development and Utility of a PAK1-Selective Degrader.
J Med Chem
; 65(23): 15627-15641, 2022 12 08.
Article
em En
| MEDLINE
| ID: mdl-36416208
ABSTRACT
Overexpression of PAK1, a druggable kinase, is common in several malignancies, and inhibition of PAK1 by small molecules has been shown to impede the growth and survival of such cells. Potent inhibitors of PAKs 1-3 have been described, but clinical development has been hindered by recent findings that PAK2 function is required for normal cardiovascular function in adult mice. A unique allosteric PAK1-selective inhibitor, NVS-PAK1-1, provides a potential path forward, but has modest potency. Here, we report the development of BJG-05-039, a PAK1-selective degrader consisting of NVS-PAK1-1 conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase substrate adaptor Cereblon. BJG-05-039 induced selective degradation of PAK1 and displayed enhanced anti-proliferative effects relative to its parent compound in PAK1-dependent, but not PAK2-dependent, cell lines. Our findings suggest that selective PAK1 degradation may confer more potent pharmacological effects compared with catalytic inhibition and highlight the potential advantages of PAK1-targeted degradation.
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1
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Dibenzazepinas
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article