2. Academic Validation
  3. Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity

Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity

  • Bioorg Chem. 2024 Jul 27:151:107679. doi: 10.1016/j.bioorg.2024.107679.
Zhenling Liu 1,  Shuqiang Mao 2,  Huixia Li 1,  Wei Liu 1,  Jing Tao 1,  Yuebing Lu 1,  Hui Dong 1,  Jie Zhang 3,  Chuanjun Song 4,  Yongtao Duan 5,  Yongfang Yao 6
Affiliations

Affiliations

  • 1 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China.
  • 2 College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
  • 3 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. Electronic address: stzhangj@263.net.
  • 4 College of Chemistry, Zhengzhou University, Zhengzhou 450001, China. Electronic address: chjsong@zzu.edu.cn.
  • 5 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China. Electronic address: duanyongtao860409@163.com.
  • 6 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou 450018, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: yongfangyao@zzu.edu.cn.
PMID: 39094510 DOI: 10.1016/j.bioorg.2024.107679
Abstract

Dual-target agents have more advantages than drug combinations for Cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 μM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human Cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 μM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell Apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/Akt pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.

Keywords

Structure-activity relation (SAR); Tubulin; Tumor; VEGFR-2.

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