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

doi:10.1016/j.heliyon.2023.e15152

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

Heliyon. 2023 Apr 19;9(5):e15152. doi: 10.1016/j.heliyon.2023.e15152. eCollection 2023 May.

Authors

Xiao Li¹, Jia Wang¹, Qianqian Wang¹, Tianwen Luo¹, Xuejiao Song², Guoquan Wan¹, Zhanzhan Feng¹, Xiaojie He¹, Qian Lei³, Ying Xu⁴, Xinyu You⁵, Luoting Yu¹, Lidan Zhang⁶, Lifeng Zhao⁷

Affiliations

¹ State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China.
² West China School of Public Health and West China Fourth Hospital, Sichuan University, 610000, China.
³ Targeted Tracer Research and Development Laboratory, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, China.
⁴ School of Chemical Engineering, Northwest University, No.229 North Taibai Road, Xi'an, Shaanxi, 710069, China.
⁵ College of Chemistry and Pharmaceutical Engineering, Huanghuai University, Zhumadian 463000, China.
⁶ Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, China.
⁷ Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, 610106, China.

Abstract

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.

Keywords: Antiangiogenic; Cancer; Mitochondrial membrane potential; Pyroptosis; ROS.