Clinical Translation of Targeted Protein Degraders.
Clin Pharmacol Ther
; 114(3): 558-568, 2023 09.
Article
em En
| MEDLINE
| ID: mdl-37399310
ABSTRACT
Targeted protein degradation (TPD) has emerged as a potentially transformational therapeutic modality with considerable promise. Molecular glue degraders remodel the surface of E3 ligases inducing interactions with neosubstrates resulting in their polyubiquitination and proteasomal degradation. Molecular glues are clinically precedented and have demonstrated the ability to degrade proteins-of-interest (POIs) previously deemed undruggable due to the absence of a traditional small molecule binding pocket. Heterobifunctional proteolysis targeting chimeras (PROTACs) possess ligands for an E3 complex and the POIs, which are chemically linked together, and similarly hijack the ubiquitin machinery to deplete the target. There has been a recent surge in the number of degraders entering clinical trials, particularly directed toward cancer. Nearly all utilize CRL4CRBN as the E3 ligase, and a relatively limited diversity of POIs are currently targeted. In this review, we provide an overview of the degraders in clinical trials and provide a perspective on the lessons learned from their development and emerging human data that will be broadly useful to those working in the TPD field.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas
/
Neoplasias
Limite:
Humans
Idioma:
En
Revista:
Clin Pharmacol Ther
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos