Discovery of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure as novel EGFR/HER-2 dual-target inhibitors against cancer growth and angiogenesis.

Abstract

Targeting EGFR and HER-2 is an essential direction for cancer treatment. Here, a series of N-(1,3,4-thiadiazol-2-yl)benzamide derivatives containing a 6,7-methoxyquinoline structure was designed and synthesized to serve as EGFR/HER-2 dual-target inhibitors. The kinase assays verified that target compounds could inhibit the kinase activity of EGFR and HER-2 selectively. The results of CCK-8 and 3D cell viability assays confirmed that target compounds had excellent anti-proliferation ability against breast cancer cells (MCF-7 and SK-BR-3) and lung cancer cells (A549 and H1975), particularly against SK-BR-3 cells, while the inhibitory effect on healthy breast cells (MCF-10A) and lung cells (Beas-2B) was weak. Among them, the hit compound YH-9 binded to EGFR and HER-2 stably in molecular dynamics studies. Further studies found thatYH-9could induce the release of cytochrome c and inhibit proliferation by promoting ROS expression in SK-BR-3 cells. Moreover,YH-9could diminish the secretion of VEGF and bFGF factors in SK-BR-3 cells, then inhibited tube formation and angiogenesis. Notably,YH-9could effectively inhibit breast cancer growth and angiogenesis with little toxicity in the SK-BR-3 cell xenograft model. Taken together,in vitroandin vivoresults revealed that YH-9 had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth and angiogenesis.

• Authors: Xin-Yang Li, De-Pu Wang, Shuai Li, Wen-Han Xue, Xin-Hua Qian, Kai-Li Liu, Yu-Heng Li, Qi-Qi Lin, Gang Dong, Fan-Hao Meng, Ling-Yan Jian
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 119 Pg. 105469 (02 2022) ISSN: 1090-2120 [Electronic] United States
• PMID: 34915285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Antineoplastic Agents
• Benzamides
• Protein Kinase Inhibitors
• Thiadiazoles
• benzamide
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzamides (chemical synthesis, chemistry, pharmacology)
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Discovery
• Drug Screening Assays, Antitumor
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Molecular Structure
• Neovascularization, Pathologic (drug therapy, pathology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship
• Thiadiazoles (chemical synthesis, chemistry, pharmacology)
• Tumor Cells, Cultured