Identification of Potent, Selective, and Orally Bioavailable Small-Molecule GSPT1/2 Degraders from a Focused Library of Cereblon Modulators.
J Med Chem
; 64(11): 7296-7311, 2021 06 10.
Article
em En
| MEDLINE
| ID: mdl-34042448
ABSTRACT
Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening and retrospective target identification efforts. Here, we describe the design, synthesis, and screening of a large diverse library of thalidomide analogues against a panel of patient-derived leukemia and medulloblastoma cell lines. These efforts led to the discovery of potent and novel GSPT1/2 degraders displaying selectivity over classical IMiD neosubstrates, such as IKZF1/3, and high oral bioavailability in mice. Taken together, this study offers compound 6 (SJ6986) as a valuable chemical probe for studying the role of GSPT1/2 in vitro and in vivo, and it supports the utility of a diverse library of CRBN binders in the pursuit of targeting undruggable oncoproteins.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Terminação de Peptídeos
/
Ubiquitina-Proteína Ligases
/
Proteínas Adaptadoras de Transdução de Sinal
/
Bibliotecas de Moléculas Pequenas
/
Proteólise
Tipo de estudo:
Diagnostic_studies
/
Observational_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article