DA-5：一种新型的氮杂吲哚基GPX4抑制剂，诱导铁下垂，用于靶向治疗癌症三阴性
DA-5: A novel azaindole-based GPX4 inhibitor inducing ferroptosis for targeted therapy of triple-negative breast cancer.
摘要(中文译文)
三阴性乳腺癌（TNBC）是一种缺乏ER、PR和HER2受体的侵袭性亚型，治疗选择有限且预后较差。铁死亡是一种由脂质过氧化驱动的铁依赖性调节性细胞死亡形式，已成为TNBC一种有前景的治疗策略。谷胱甘肽过氧化物酶4（GPX4）是铁死亡的关键抑制因子，抑制其活性可使TNBC细胞对氧化损伤敏感。为发现并表征DA-5——一种受中药舒肝宁注射液（SGNI）中化合物启发而设计的新型3,5-二取代氮杂吲哚衍生物——作为强效GPX4抑制剂诱导TNBC细胞铁死亡的作用。采用分子对接和结构优化设计DA-5。评估其与GPX4的结合亲和力（K）和酶抑制活性（IC）。通过体外实验评估DA-5通过脂质过氧化诱导TNBC细胞铁死亡的能力，同时评估其对正常乳腺上皮细胞的影响。通过口服给药在TNBC异种移植模型中评估DA-5的体内疗效和安全性。同时分析药代动力学特征。DA-5表现出与GPX4的高亲和力结合（K = 10.04 μM），并有效抑制其酶活性（IC = 10.90 μM）。在TNBC细胞中，DA-5促进脂质过氧化并诱导铁死亡，而铁死亡抑制剂和铁螯合剂可逆转此效应。口服给予DA-5可显著抑制体内TNBC异种移植瘤生长，且无全身毒性，并具有良好的药代动力学和安全性特征。这些发现表明DA-5是一种新型氮杂吲哚类GPX4抑制剂，能够通过靶向GPX4的脂质过氧化诱导铁死亡。这一突破为TNBC提供了一种有前景的靶向治疗策略。
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype lacking the ER, PR, and HER2 receptors, with limited treatment options and poor prognosis. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic strategy for TNBC. Glutathione peroxidase 4 (GPX4) is a key ferroptosis suppressor, and its inhibition sensitizes TNBC cells to oxidative damage. To discover and characterize DA-5, a novel 3,5-disubstituted azaindole derivative inspired by compounds from the traditional Chinese medicine Shuganning injection (SGNI), as a potent GPX4 inhibitor to induce ferroptosis in TNBC cells. Molecular docking and structural optimization were used to design DA-5. Its binding affinity (K) and enzymatic inhibitory activity (IC) against GPX4 were evaluated. In vitro assays assessed DA-5's ability to induce ferroptosis in TNBC cells through lipid peroxidation while sparing normal mammary epithelial cells. In vivo studies evaluated the efficacy and safety of DA-5 in TNBC xenograft models via oral administration. Pharmacokinetic profiles were also analyzed. DA-5 demonstrated high-affinity binding to GPX4 (K = 10.04 μM) and effectively suppressed its enzymatic activity (IC = 10.90 μM). In TNBC cells, DA-5 promoted lipid peroxidation and induced ferroptosis, which was rescued by ferroptosis inhibitors and by iron chelators. Oral administration of DA-5 significantly inhibited TNBC xenograft growth in vivo without systemic toxicity, supported by favorable pharmacokinetic and safety profiles. These findings identify DA-5 as a novel azaindole-based GPX4 inhibitor capable of inducing ferroptosis through GPX4-targeted lipid peroxidation. This breakthrough offers a promising targeted therapy for TNBC.
如何引用
AMA
Jingjing Du, Kaiqiang Guo, ChaoJie Wang, Xuening Zhang, Yanchao Yang, Tong Chu, et al. DA-5: A novel azaindole-based GPX4 inhibitor inducing ferroptosis for targeted therapy of triple-negative breast cancer.. Bioorganic chemistry. 2026; doi:10.1016/j.bioorg.2026.109901.
APA
Jingjing Du, Kaiqiang Guo, ChaoJie Wang, Xuening Zhang, Yanchao Yang, Tong Chu, et al (2026). DA-5: A novel azaindole-based GPX4 inhibitor inducing ferroptosis for targeted therapy of triple-negative breast cancer.. Bioorganic chemistry. https://doi.org/10.1016/j.bioorg.2026.109901
GB/T 7714
Jingjing Du, Kaiqiang Guo, ChaoJie Wang, Xuening Zhang, Yanchao Yang, Tong Chu, et al. DA-5: A novel azaindole-based GPX4 inhibitor inducing ferroptosis for targeted therapy of triple-negative breast cancer.[J]. Bioorganic chemistry, 2026 doi:10.1016/j.bioorg.2026.109901.
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