2. Academic Validation
  3. Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments

Discovery of the Inhibitor Targeting the SLC7A11/xCT Axis through In Silico and In Vitro Experiments

  • Int J Mol Sci. 2024 Jul 29;25(15):8284. doi: 10.3390/ijms25158284.
Jianda Yue 1 2 3,  Yekui Yin 1 2 3,  Xujun Feng 1 2 3,  Jiawei Xu 1 2 3,  Yaqi Li 1 2 3,  Tingting Li 1 2 3,  Songping Liang 1 2 3,  Xiao He 4 5 6,  Zhonghua Liu 1 2 3,  Ying Wang 1 2 3
Affiliations

Affiliations

  • 1 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China.
  • 2 Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha 410081, China.
  • 3 Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, China.
  • 4 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 5 Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 6 New York University-East China Normal University Center for Computational Chemistry, New York University Shanghai, Shanghai 200062, China.
PMID: 39125853 DOI: 10.3390/ijms25158284
Abstract

In the development and progression of cervical Cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical Cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits Ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical Cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical Cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and Reactive Oxygen Species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical Cancer both in vitro and in silico.

Keywords

SLC7A11/xCT axis; cervical cancer; drug discovery; oxidative stress; virtual screening and molecular dynamics simulation.

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