Discovery of HyT-Based Degraders of CDK9-Cyclin T1 Complex.
Chem Biodivers
; 20(8): e202300769, 2023 Aug.
Article
em En
| MEDLINE
| ID: mdl-37349855
ABSTRACT
Direct modulation of the non-kinase functions of cyclin and CDK-cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC50 values of 0.362â
µM against CDK9 and 0.680â
µM against cyclin T1. In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Núcleo Celular
/
Ciclinas
Limite:
Humans
/
Male
Idioma:
En
Revista:
Chem Biodivers
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China