2. Academic Validation
  3. Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer

Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer

  • Eur J Med Chem. 2021 Jan 15:210:112980. doi: 10.1016/j.ejmech.2020.112980.
Wu-Xi Zhou 1,  Chen Chen 1,  Xiao-Qin Liu 1,  Ying Li 1,  Yao-Lan Lin 1,  Xiu-Tao Wu 1,  Ling-Yi Kong 2,  Jian-Guang Luo 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: lykong@cpu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China. Electronic address: luojg@cpu.edu.cn.
PMID: 33176943 DOI: 10.1016/j.ejmech.2020.112980
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.

Keywords

Antitumor; GLS1 inhibitors; Molecular docking; TNBC; Withangulatin A derivatives.

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