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

Tai Li; Jiawei Wang; Limiao Feng; Qi Zhou; Qian Xie; Yanni Shen; Rongxin Ji; Xiaoping Liu; Yan Wang; Chun Hu

doi:10.1016/j.bioorg.2024.107358

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

Bioorg Chem. 2024 Apr 9:147:107358. doi: 10.1016/j.bioorg.2024.107358. Online ahead of print.

Authors

Tai Li¹, Jiawei Wang¹, Limiao Feng¹, Qi Zhou¹, Qian Xie², Yanni Shen², Rongxin Ji¹, Xiaoping Liu³, Yan Wang⁴, Chun Hu⁵

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.