Design, Synthesis, and Biological Evaluation of Eukaryotic Initiation Factor 2B (eIF2B) Activators.
ChemMedChem
; 19(11): e202300716, 2024 Jun 03.
Article
en En
| MEDLINE
| ID: mdl-38426720
ABSTRACT
The eukaryotic initiation factor 2B (eIF2B) is a key regulator in protein-regulated signaling pathways and is closely related to the function of the central nervous system. Modulating eIF2B could retard the process of neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and vanishing white matter disease (VWM) etâ
al. Here, we designed and synthesized a series of novel eIF2B activators containing oxadiazole fragments. The activating effects of compounds on eIF2B were investigated through testing the inhibition of ATF4 expression. Of all the targeted compounds, compoundsâ
21 and 29 exhibited potent inhibition on ATF4 expression with IC50 values of 32.43â
nM and 47.71â
nM, respectively, which were stronger than that of ISRIB (IC50=67.90â
nM). ATF4 mRNA assay showed that these two compounds could restore ATF4 mRNA to normal levels in thapsigargin-stimulated HeLa cells. Protein Translation assay showed that both compounds were effective in restoring protein synthesis. Compound potency assay showed that both compounds had similar potency to ISRIB with EC50 values of 5.844 and 37.70â
nM. Cytotoxicity assay revealed that compounds 21 and 29 had low toxicity and were worth further investigation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Factor 2B Eucariótico de Iniciación
/
Factor de Transcripción Activador 4
Límite:
Humans
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2024
Tipo del documento:
Article