期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 210, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112980
关键词
Withangulatin A derivatives; GLS1 inhibitors; Molecular docking; Antitumor; TNBC
资金
- National Natural Science Foundation of China [81872983]
- Natural Science Foundation of Jiangsu Province [BK20181329]
- Drug Innovation Major Project [2018ZX09711-001-007]
A potential novel GLS1 inhibitor has been developed through synthesis and optimization, showing effective therapeutic effects on triple-negative breast cancer. The inhibitor induces apoptosis in MDA-MB-231 cells by influencing metabolic pathways. Animal model experiments demonstrate significant therapeutic effects of the inhibitor.
To develop novel GLS1 inhibitors as effective therapeutic agents for triple-negative breast cancer (TNBC), 25 derivatives were synthesized from the natural inhibitor withangulatin A (IC50 = 18.2 mM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 mu M). In MDA-MB-231 cells, 7 diminished cellular glutamate levels by blocking glutaminolysis pathway, further triggering the generation of reactive oxygen species to induce caspase-dependent apoptosis. Molecular docking indicated that 7 interacted with a new reacting site of allosteric binding pocket by forming various interactions in GLS1. The intraperitoneal administration of 7 at a dose of 50 mg/kg exhibited remarkable therapeutic effects and no apparent toxicity in the MDA-MB-231 xenograft model, indicating its potential as a novel GLS1 inhibitor for treatment of TNBC. (C) 2020 Elsevier Masson SAS. All rights reserved.
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