Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking.
J Am Chem Soc
; 142(11): 4960-4964, 2020 03 18.
Article
em En
| MEDLINE
| ID: mdl-32105459
ABSTRACT
Eukaryotic translation initiation factor 4E (eIF4E) binds the m7GTP cap structure at the 5'-end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis. eIF4E is a notoriously challenging target, and most of the reported inhibitors are negatively charged guanine analogues with negligible cell permeability. To overcome these challenges, we envisioned a covalent targeting strategy. As there are no cysteines near the eIF4E cap binding site, we developed a covalent docking approach focused on lysine. Taking advantage of a "make-on-demand" virtual library, we used covalent docking to identify arylsulfonyl fluorides that target a noncatalytic lysine (Lys162) in eIF4E. Guided by cocrystal structures, we elaborated arylsulfonyl fluoride 2 to 12, which to our knowledge is the first covalent eIF4E inhibitor with cellular activity. In addition to providing a new tool for acutely inactivating eIF4E in cells, our computational approach may offer a general strategy for developing selective lysine-targeted covalent ligands.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
/
Fator de Iniciação 4E em Eucariotos
/
Lisina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Am Chem Soc
Ano de publicação:
2020
Tipo de documento:
Article