The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest

  • Cell Death Dis. 2023 Jan 9;14(1):11. doi: 10.1038/s41419-022-05528-8.
Wenpeng Zhao  1 ,  Liang Zhang  1 ,  Yaya Zhang  2 ,  Zhengye Jiang  1 ,  Hanwen Lu  1 ,  Yuanyuan Xie  1 ,  Wanhong Han  1 ,  Wentao Zhao  1  3 ,  Jiawei He  1 ,  Zhongjie Shi  1 ,  Huiying Yang  1 ,  Junjie Chen  4 ,  Sifang Chen  1 ,  Zhangyu Li  1 ,  Jianyao Mao  1 ,  Liwei Zhou  1 ,  Xin Gao  1 ,  Wenhua Li  1 ,  Guowei Tan  1 ,  Bingchang Zhang  5 ,  Zhanxiang Wang  6
Affiliations
  • 1. Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China.
  • 2. Department of Medical Oncology, the First Affiliated Hospital of Xiamen University, Xiamen, 361003, China.
  • 3. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 4. Analysis and Measurement Center, School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361001, P. R. China.
  • 5. Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China. [email protected].
  • 6. Department of Neurosurgery and Department of Neuroscience, Fujian Key Laboratory of Brain Tumors Diagnosis and Precision Treatment, Xiamen Key Laboratory of Brain Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361102, China. [email protected].
PMID: 36624090 DOI: 10.1038/s41419-022-05528-8
Abstract

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor with a poor median survival of less than 15 months. However, clinical strategies and effective therapies are limited. Here, we found that the second-generation small molecule multi-CDK inhibitor AT7519 is a potential drug for GBM treatment according to high-throughput screening via the Approved Drug Library and Clinical Compound Library (2718 compounds). We found that AT7519 significantly inhibited the cell viability and proliferation of U87MG, U251, and patient-derived primary GBM cells in a dose-dependent manner. Furthermore, AT7519 also inhibited the phosphorylation of CDK1/2 and arrested the cell cycle at the G1-S and G2-M phases. More importantly, AT7519 induced intrinsic Apoptosis and Pyroptosis via caspase-3-mediated cleavage of gasdermin E (GSDME). In the glioblastoma intracranial and subcutaneous xenograft assays, tumor volume was significantly reduced after treatment with AT7519. In summary, AT7519 induces cell death through multiple pathways and inhibits glioblastoma growth, indicating that AT7519 is a potential chemical available for GBM treatment.

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