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Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer
- Source :
- European Journal of Medicinal Chemistry. 210:112980
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- 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 μM). Bioassay optimization identified a novel and selective GLS1 inhibitor 7 (IC50 = 1.08 μM). 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.
- Subjects :
- Cell Survival
Allosteric regulation
Antineoplastic Agents
Triple Negative Breast Neoplasms
01 natural sciences
Structure-Activity Relationship
03 medical and health sciences
Glutaminase
Cell Line, Tumor
Drug Discovery
Humans
Bioassay
Enzyme Inhibitors
Triple-negative breast cancer
Cell Proliferation
030304 developmental biology
Pharmacology
chemistry.chemical_classification
0303 health sciences
Reactive oxygen species
Glutaminolysis
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Organic Chemistry
Pregnenes
General Medicine
0104 chemical sciences
chemistry
Apoptosis
Toxicity
Cancer research
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 210
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....be1268f05204259b6401884c0c855765