Heliyon (May 2023)

A novel VEGFR inhibitor ZLF-095 with potent antitumor activity and low toxicity

  • Xiao Li,
  • Jia Wang,
  • Qianqian Wang,
  • Tianwen Luo,
  • Xuejiao Song,
  • Guoquan Wan,
  • Zhanzhan Feng,
  • Xiaojie He,
  • Qian Lei,
  • Ying Xu,
  • Xinyu You,
  • Luoting Yu,
  • Lidan Zhang,
  • Lifeng Zhao

Journal volume & issue
Vol. 9, no. 5
p. e15152

Abstract

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Angiogenesis plays a critical role in the survival, progression and metastasis of malignant tumors. Multiple factors are known to induce tumor angiogenesis, vascular endothelial growth factor (VEGF) is the most important one. Lenvatinib is an oral multi-kinase inhibitor of VEGFRs which has been approved for the treatment of various malignancies as the first-line agent by the Food and Drug Administration (FDA). It shows excellent antitumor efficacy in clinical practice. However, the adverse effects of Lenvatinib may seriously impair the therapeutic effect. Here we report the discovery and characterization of a novel VEGFR inhibitor (ZLF-095), which exhibited high activity and selectivity for VEGFR1/2/3. ZLF-095 displayed apparently antitumor effect in vitro and in vivo. We discovered that Lenvatinib could provoke fulminant ROS-caspase3-GSDME-dependent pyroptosis in GSDME-expressing cells by loss of mitochondrial membrane potential, which may be one of the reasons for Lenvatinib's toxicity. Meanwhile, ZLF-095 showed less toxicity than Lenvatinib by switching pyroptosis to apoptosis. These results suggest that ZLF-095 could become a potential angiogenesis inhibitor for cancer therapy.

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