Metabolomics-assisted discovery of a new anticancer GLS-1 inhibitor chemotype from a nortopsentin-inspired library: From phenotype screening to target identification.

Autor: Carbone D; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy., Vestuto V; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Ferraro MR; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy., Ciaglia T; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Pecoraro C; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy., Sommella E; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Cascioferro S; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy., Salviati E; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Novi S; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Tecce MF; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Amodio G; Department of Medicine, Surgery and Dentistry 'Scuola Medica Salernitana'/DIPMED, Via S. Allende, 84081, Baronissi, SA, Italy., Iraci N; Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Ferdinando Stagno d'Alcontres 31, 98166, Messina, Italy., Cirrincione G; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy., Campiglia P; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Diana P; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy., Bertamino A; Department of Pharmacy, University of Salerno, Via G. Paolo II, 84084, Fisciano, SA, Italy., Parrino B; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123, Palermo, Italy. Electronic address: barbara.parrino@unipa.it., Ostacolo C; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131, Naples, Italy. Electronic address: ostacolo@unina.it.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2022 Apr 15; Vol. 234, pp. 114233. Date of Electronic Publication: 2022 Mar 06.
DOI: 10.1016/j.ejmech.2022.114233
Abstrakt: 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 (IC 50  = 3.96 ± 1.05 μM), compared to the GLS-2 isoform (IC 50  = 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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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