Targeting CDK4 with repurposing perphenazine inhibited the growth of gastric cancer AGS and HGC27 cells by arresting cell cycle

  • Biochem Pharmacol. 2026 Sep;251(Pt 1):118133. doi: 10.1016/j.bcp.2026.118133.
Yunhao Ma  1 ,  Yanan Tian  2 ,  Haiyan Wang  3 ,  Hongxia Zhang  4 ,  Yixuan Li  5 ,  Zhongkun Zhou  1 ,  Zhenzhen Si  1 ,  Yuanchun Zhao  1 ,  Yan Jin  1 ,  Baizhuo Zhang  1 ,  Hong Fang  1 ,  Huanxiang Liu  2 ,  Hongmei Zhu  5 ,  Yingqian Liu  6 ,  Peng Chen  7
Affiliations
  • 1. School of Pharmacy, Lanzhou University, No. 199 Donggang West Road, Lanzhou 730000, PR China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, PR China.
  • 2. Faculty of Applied Sciences, Macao Polytechnic University, Macao, SAR, PR China.
  • 3. College of Pastoral Agriculture Science and Technology, Lanzhou University, No. 768 West Jiayuguan Road, Lanzhou 730020, PR China.
  • 4. Department of Gastroenterology, Sanaitang Hospital, No. 72 Jingning Road, Lanzhou 730030, PR China.
  • 5. School of Pharmacy, Lanzhou University, No. 199 Donggang West Road, Lanzhou 730000, PR China.
  • 6. School of Pharmacy, Lanzhou University, No. 199 Donggang West Road, Lanzhou 730000, PR China. Electronic address: [email protected].
  • 7. School of Pharmacy, Lanzhou University, No. 199 Donggang West Road, Lanzhou 730000, PR China; State Key Laboratory of Applied Organic Chemistry, Lanzhou University, No. 222 South Tianshui Road, Lanzhou 730000, PR China. Electronic address: [email protected].
PMID: 42242504 DOI: 10.1016/j.bcp.2026.118133
Abstract

Gastric Cancer (GC) is an important malignancy worldwide and remains a significant cause for cancer-related mortality globally. Drug repositioning provides opportunities for drug development to reduce the cost and time inherent in the original drug development process and the risk of depletion. Bioinformatics analysis revealed that the protein and mRNA expression level of cyclin dependent kinase 4 (CDK4) in patients' tissues of gastric Cancer was significantly higher than that in normal tissues. Present study found that the docking score of CDK4 protein with perphenazine was best determined through virtual screening of CDK4 protein and 511 drugs. Perphenazine inhibited the proliferation of tumor in mouse-derived tumor model, induced the death of human gastric Cancer organoids. Perphenazine showed good inhibitory effect in gastric Cancer AGS and HGC27 cells, with IC50 of AGS and HGC27 cells reaching 6.60 ± 0.34 μM and 12.25 ± 1.44 μM. Perphenazine inhibited colony formation, proliferation and migration of AGS and HGC27 cells. Moreover, perphenazine induced cells Apoptosis by mitochondrial dysfunction of gastric Cancer AGS and HGC27 cells. Besides, AGS and HGC27 cells at the G0/G1 phase were arrested after treatment of perphenazine. Palbociclib significantly enhanced this effect, while INK4C-IN-2 significantly reversed this blocking effect. In summary, we found a novel anti-tumor indication of antipsychotic drug perphenazine, which can inhibit the growth of tumor in vitro and in mouse-derived tumor model. These results suggested that perphenazine is also a promising anti-gastric Cancer drug in clinical applications.

Keywords
CDK4; Drug repositioning; Gastric cancer; Perphenazine; Xenograft model.
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