1. Design, synthesis and biological evaluation of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors bearing a heterocyclic-containing tail as potential anti-tumor agents.
- Author
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Hao S, Wang JH, Hou L, Liang JW, Yan JH, Niu YF, Li XY, Sun Q, and Meng FH
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Animals, Mice, Cell Line, Tumor, Molecular Docking Simulation, Apoptosis drug effects, Heterocyclic Compounds pharmacology, Heterocyclic Compounds chemistry, Heterocyclic Compounds chemical synthesis, Female, ErbB Receptors antagonists & inhibitors, ErbB Receptors metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Quinazolines pharmacology, Quinazolines chemistry, Quinazolines chemical synthesis, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Drug Design, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Dose-Response Relationship, Drug
- Abstract
A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC
50 ) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth., 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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