2. Academic Validation
  3. Discovery of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors with anti-angiogenic properties

Discovery of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors with anti-angiogenic properties

  • Bioorg Chem. 2024 Jun:147:107358. doi: 10.1016/j.bioorg.2024.107358.
Tai Li 1,  Jiawei Wang 1,  Limiao Feng 1,  Qi Zhou 1,  Qian Xie 2,  Yanni Shen 2,  Rongxin Ji 1,  Xiaoping Liu 3,  Yan Wang 4,  Chun Hu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, 110016, China.
  • 2 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, 110016, China; Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 3 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, 110016, China. Electronic address: lxp19730107@163.com.
  • 4 Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China. Electronic address: yan.wang@siat.ac.cn.
  • 5 Key Laboratory of Structure-based Drug Design & Discovery (Ministry of Education), Shenyang Pharmaceutical University, 110016, China. Electronic address: chunhu@syphu.edu.cn.
PMID: 38626490 DOI: 10.1016/j.bioorg.2024.107358
Abstract

VEGFR-2 is an attractive target for the development of anti-tumor drugs and plays a crucial role in tumor angiogenesis. This study reports a series of novel thiophene-3-carboxamide derivatives based on PAN-90806 as VEGFR-2 inhibitors, among which compound 14d exhibits excellent anti-proliferative activity against HCT116, MCF7, PC3, and A549 cell lines, and has effective VEGFR-2 inhibitory activity with an IC50 value of 191.1 nM. Additionally, CETSA results indicated that VEGFR-2 was a relevant target of compound 14d in the cell lines, and compound 14d could also inhibit VEGFR-2 protein phosphorylation in A549 cell line. Furthermore, compound 14d inhibited colony formation, cell migration, and HUVECs tube formation in a dose-dependent manner. The mechanism by which 14d induced Cancer cell death involves blocking the cell cycle, increasing ROS production, inducing Apoptosis, and dose-dependently reducing the levels of phosphorylated ERK and MEK. Molecular docking and molecular dynamics simulations had shown that compound 14d could stably bind to the active site of VEGFR-2. These results confirmed that compound 14d might be a promising lead compound for anti-angiogenesis.

Keywords

Anti-angiogenesis; Anticancer; CETSA; PAN-90806; VEGFR-2.

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