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Bioorg Chem ; 147: 107358, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38626490

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.


Subject(s)
Angiogenesis Inhibitors , Antineoplastic Agents , Cell Proliferation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Protein Kinase Inhibitors , Thiophenes , Vascular Endothelial Growth Factor Receptor-2 , Humans , 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 , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Molecular Structure , Drug Discovery , Cell Movement/drug effects , Apoptosis/drug effects , Molecular Docking Simulation , Cell Line, Tumor
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