Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification.
Eur J Med Chem
; 234: 114233, 2022 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-35286926
The enzyme glutaminase-1 (GLS-1) has shown a clear and coherent implication in the progression and exacerbation of different aggressive tumors such as glioblastoma, hepatocarcinoma, pancreas, bone, and triple-negative breast cancer. Few chemotypes are currently available as selective GLS-1 inhibitors, and still, fewer of them are at the clinical stage. In the present paper, starting from a naturally-inspired antitumor compound library, metabolomics has been used to putatively identify the molecular mechanism underlying biological activity. GLS-1 was identified as a potential target. Biochemical analysis confirmed the hypothesis leading to the identification of a new hit compound acting as a GLS-1 selective inhibitor (IC50 = 3.96 ± 1.05 µM), compared to the GLS-2 isoform (IC50 = 12.90 ± 0.87 µM), with remarkable antitumor potency over different aggressive tumor cell lines. Molecular modelling studies revealed new insight into the drug-target interaction providing robust SAR clues for the rational hit-to-lead development. The approach undertaken underlines the wide potential of metabolomics applied to drug discovery, particularly in target identification and hit discovery following phenotype screening.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama Triple Negativas
/
Glutaminasa
Tipo de estudio:
Diagnostic_studies
/
Screening_studies
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2022
Tipo del documento:
Article
País de afiliación:
Italia