1. Discovery of novel thiophene-3-carboxamide derivatives as potential VEGFR-2 inhibitors with anti-angiogenic properties.
- Author
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Li T, Wang J, Feng L, Zhou Q, Xie Q, Shen Y, Ji R, Liu X, Wang Y, and Hu C
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Drug Discovery, Cell Movement drug effects, Apoptosis drug effects, Molecular Docking Simulation, Cell Line, Tumor, Vascular Endothelial Growth Factor Receptor-2 antagonists & inhibitors, Vascular Endothelial Growth Factor Receptor-2 metabolism, Thiophenes pharmacology, Thiophenes chemistry, Thiophenes chemical synthesis, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors chemistry, Angiogenesis Inhibitors chemical synthesis, Cell Proliferation drug effects, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors chemical synthesis, Drug Screening Assays, Antitumor, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Dose-Response Relationship, Drug
- 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 IC
50 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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