Discovery of new HER2/EGFR dual kinase inhibitors based on the anilinoquinazoline scaffold as potential anti-cancer agents

Sadek M.M.; Serrya R.A.; Kafafy A.-H.N.; Ahmed M.; Wang F.; Abouzid K.A.M.

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Discovery of new HER2/EGFR dual kinase inhibitors based on the anilinoquinazoline scaffold as potential anti-cancer agents

Sadek M.M.; Serrya R.A.; Kafafy A.-H.N.; Ahmed M.; Wang F.; Abouzid K.A.M.

Full Text link: https://t.ly/zN55V

Date issued: 2014

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Doi: https://doi.org/10.3109/14756366.2013.765417 PubMed ID 23402383

Publisher: Informa Healthcare

Series Info: Journal of Enzyme Inhibition and Medicinal Chemistry
29

Type: Article

Keywords: Anilinoquinazoline , EGFR , HER2 , Kinase inhibitors , Lapatinib , antineoplastic agent , epidermal growth factor receptor , epidermal growth factor receptor 2 , molecular scaffold , phosphotransferase inhibitor , quinazoline derivative , staurosporine , antiproliferative activity , article , cancer cell culture , drug activity , drug design , drug synthesis , enzyme inhibition , human , IC 50 , molecular model , priority journal , Aniline Compounds , Antineoplastic Agents , Cell Line, Tumor , Cell Proliferation , Cell Survival , Drug Discovery , Humans , Molecular Docking Simulation , Molecular Structure , Protein Kinase Inhibitors , Quinazolines , Receptor, Epidermal Growth Factor , Receptor, erbB-2

Abstract:

Herein, we designed and synthesized certain anilinoquinazoline derivatives bearing bulky arylpyridinyl, arylpropenoyl and arylpyrazolyl moieties at the 4? position of the anilinoquinazoline, as potential dual HER2/EGFR kinase inhibitors. A detailed molecular modeling study was performed by docking the synthesized compounds in the active site of the epidermal growth factor receptor (EGFR). The synthesized compounds were further tested for their inhibitory activity on EGFR and HER2 tyrosine kinases. The aryl 2-imino-1,2-dihydropyridine derivatives 5d and 5e displayed the most potent inhibitory activity on EGFR with IC50 equal to 2.09 and 1.94 ?M, respectively, and with IC50 equal to 3.98 and 1.04 ?M on HER2, respectively. Furthermore, the anti-proliferative activity of these most active compounds on MDA-MB-231 breast cancer cell lines, known to overexpress EGFR, showed an IC50 range of 2.4 and 2.5 ?M, respectively. � 2014 Informa UK Ltd. All rights reserved.