1. Design, synthesis and biological evaluation of novel 4-aminoquinazolines as dual target inhibitors of EGFR-PI3Kα.
- Author
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Ding HW, Deng CL, Li DD, Liu DD, Chai SM, Wang W, Zhang Y, Chen K, Li X, Wang J, Song SJ, and Song HR
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Class I Phosphatidylinositol 3-Kinases metabolism, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, ErbB Receptors metabolism, Humans, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Quinazolines chemical synthesis, Quinazolines chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Drug Design, ErbB Receptors antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Quinazolines pharmacology
- Abstract
The overexpression of EGFR correlates with rapidly progressive disease, resistance to chemotherapy and poor prognosis. In certain human cancers, PI3K works synergistically with EGFR to promote proliferation, survival, invasion and metastasis. Development of dual-target drugs against EGFR and PI3K has therapeutic advantage and was an attractive approach against tumors. In this work, based on the molecular docking and previous studies, a series of 4-aminoquinazolines derivatives containing 6-sulfonamide substituted pyridyl group were rationally designed and identified as potent EGFR and PI3K dual inhibitors. The cytotoxicity experiment results showed that this series of compounds could effectively inhibit cell growth. The kinase assay demonstrated that 6c and 6i had high inhibition for EGFR and selectivity for PI3Kα distinguished from other isoforms. Further experiments showed that 6c could induce cell cycle arrest in G1 phase and apoptosis in BT549 cells. The western blot assay indicated that 6c inhibited the proliferation of BT549 cell through EGFR and PI3Kα/Akt signaling pathway. Our study suggested that compound 6c was a potential dual inhibitors of EGFR and PI3Kα., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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