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

• DOI: 10.1016/j.ejmech.2022.114233
• Publication Date: 2022-03-07T04:03:14Z
• Authors: Daniela Carbone; Vincenzo Vestuto; Maria Rosalia Fer...; 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
• Keywords: 0301 basic medicine; Anticancer agents, GLS-1 inhibitors, Marine alkaloids, Metabolomics, Nortopsentin analogues; Nortopsentin analogues; Anticancer agents; GLS-1 inhibitors; Marine alkaloids; Metabolomics; Nortopsentin analogues; Triple Negative Breast Neoplasms; 3. Good health; 03 medical and health sciences; Phenotype; Marine alkaloids; Glutaminase; Anticancer agents; Cell Line, Tumor; Humans; Metabolomics; Nortopsentin analogues; Marine alkaloids; GLS-1 inhibitors; Anticancer agents; Metabolomics; GLS-1 inhibitors

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.