Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification
| Autor: | Daniela Carbone, Vincenzo Vestuto, Maria Rosalia Ferraro, Tania Ciaglia, Camilla Pecoraro, Eduardo Sommella, Stella Cascioferro, Emanuela Salviati, Sara Novi, Mario Felice Tecce, Giuseppina Amodio, Nunzio Iraci, Girolamo Cirrincione, Pietro Campiglia, Patrizia Diana, Alessia Bertamino, Barbara Parrino, Carmine Ostacolo |
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| Přispěvatelé: | Carbone D., Vestuto V., Ferraro M.R., Ciaglia T., Pecoraro C., Sommella E., Cascioferro S., Salviati E., Novi S., Tecce M.F., Amodio G., Iraci N., Cirrincione G., Campiglia P., Diana P., Bertamino A., Parrino B., Ostacolo C., Carbone, Daniela, Vestuto, Vincenzo, Ferraro, Maria Rosalia, Ciaglia, Tania, Pecoraro, Camilla, Sommella, Eduardo, Cascioferro, Stella, Salviati, Emanuela, Novi, Sara, Tecce, Mario Felice, Amodio, Giuseppina, Iraci, Nunzio, Cirrincione, Girolamo, Campiglia, Pietro, Diana, Patrizia, Bertamino, Alessia, Parrino, Barbara, Ostacolo, Carmine |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Organic Chemistry Nortopsentin analogue Nortopsentin analogues Triple Negative Breast Neoplasms Anticancer agents GLS-1 inhibitors Marine alkaloids Metabolomics General Medicine Settore CHIM/08 - Chimica Farmaceutica Phenotype Anticancer agent Glutaminase Cell Line Tumor Drug Discovery Humans Marine alkaloid GLS-1 inhibitor |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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