Discovery and Optimization of Ergosterol Peroxide Derivatives as Novel Glutaminase 1 Inhibitors for the Treatment of Triple-Negative Breast Cancer

被引:4
作者
Luo, Ran [1 ]
Zhao, Haoyi [1 ]
Deng, Siqi [1 ]
Wu, Jiale [2 ]
Wang, Haijun [1 ]
Guo, Xiaoshan [1 ]
Han, Cuicui [1 ]
Ren, Wenkang [1 ]
Han, Yinglong [1 ]
Zhou, Jianwen [3 ]
Lin, Yu [1 ]
Bu, Ming [1 ]
机构
[1] Qiqihar Med Univ, Coll Pharm, Qiqihar 161006, Peoples R China
[2] Hainan Univ, Coll Pharm, Haikou 570228, Peoples R China
[3] Qiqihar Med Univ, Res Inst Med & Pharm, Qiqihar 161006, Peoples R China
来源
MOLECULES | 2024年 / 29卷 / 18期
关键词
ergosterol peroxide derivatives; GLS1; inhibitors; antitumor; TNBC; PHOSPHATE-DEPENDENT GLUTAMINASE; CELL-GROWTH; METABOLISM; APOPTOSIS;
D O I
10.3390/molecules29184375
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound 3g exhibited the most potent antiproliferative activity, with an IC50 value of 3.20 mu M against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified 3g as a novel glutaminase 1 (GLS1) inhibitor (IC50 = 3.77 mu M). In MDA-MB-231 cells, 3g reduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that 3g interacts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer, 3g showed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results, 3g could be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.
引用
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页数:24
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