DA-5: A novel azaindole-based GPX4 inhibitor inducing ferroptosis for targeted therapy of triple-negative breast cancer

  • Bioorg Chem. 2026 Aug 5:177:109901. doi: 10.1016/j.bioorg.2026.109901.
Jingjing Du  1 ,  Kaiqiang Guo  2 ,  ChaoJie Wang  3 ,  Xuening Zhang  4 ,  Yanchao Yang  4 ,  Tong Chu  4 ,  Dongfan Yang  4 ,  Dayuan Zheng  4 ,  Wenzhe Ma  5
Affiliations
  • 1. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China; Nanhu Laboratory, Jiaxing 314051, Zhejiang, China.
  • 2. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China.
  • 3. Jiangxi Cancer Hospital (The Second Affiliated Hospital of Nanchang Medical Colloge), Nanchang 330029, Jiangxi, China.
  • 4. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China; Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Hengqin Guangdong-Macao In-Depth Cooperation Zone, Zhuhai 519099, Guangdong, China.
  • 5. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China; Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Hengqin Guangdong-Macao In-Depth Cooperation Zone, Zhuhai 519099, Guangdong, China. Electronic address: [email protected].
PMID: 42048687 DOI: 10.1016/j.bioorg.2026.109901
Abstract

Background: 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.

Purpose: 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.

Methods: Molecular docking and structural optimization were used to design DA-5. Its binding affinity (Kd) and enzymatic inhibitory activity (IC50) 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.

Results: DA-5 demonstrated high-affinity binding to GPX4 (Kd = 10.04 μM) and effectively suppressed its enzymatic activity (IC50 = 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.

Conclusion: 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.

Keywords
DA-5; Ferroptosis; GPX4; Shuganning injection (SGNI); Triple-negative breast cancer.
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