Discovery of novel 4-anilinoquinazoline derivatives as potent inhibitors of epidermal growth factor receptor with antitumor activity

College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 07/2013; 21(19). DOI: 10.1016/j.bmc.2013.06.070
Source: PubMed


Two new series of new compounds containing a 6-amino-substituted group or 6-acrylamide-substituted group linked to a 4-anilinoquinazoline nucleus have been discovered as potential EGFR inhibitors. These compounds proved efficient effects on antiproliferative activity and EGFR-TK inhibitory activity. Especially, N(6)-((5-bromothiophen-2-yl)methyl)-N(4)-(3-chlorophenyl)quinazoline-4,6-diamine (5e), showed the most potent inhibitory activity (IC50=3.11μM for Hep G2, IC50=0.82μM for A549). The EGFR molecular docking model suggested that the new compound is nicely bound to the region of EGFR, and cell morphology by Hoechst stain experiment suggested that these compounds efficiently induced apoptosis of A549 cells.

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    ABSTRACT: Introduction: The signaling pathways downstream of epidermal growth factor receptor (EGFR) are central to the biology of colorectal cancer. EGFR kinase represents an attractive target for the development of novel therapies for the treatment of cancers. A considerable achievement during the past 2 years was the development of targeted therapies against EGFR using small-molecule inhibitors such as quinazoline derivatives, pyrimidine derivatives, thiazole derivatives, acrylamide derivatives and urea derivatives. Some new methods and technologies were also used to discover novel reversible and irreversible EGFR inhibitors. In this review, recent advances in the research of EGFR inhibitors are reviewed. Areas covered: This review summarized new patents and articles published on EGFR inhibitors within 2010 to present. Expert opinion: From 2010 to present, some novel scaffolds have been discovered as first-generation EGFR inhibitors, which are more potent against both EGFR-activating (EGFR WT) and resistance mutations (EGFRDM, T790M/L858R). 'Fast-Forwarding Hit to Lead' and 'Combi-Molecule' postulate to represent a novel approach to cancer therapy. The focus on irreversible inhibitors is also of significance for the design of kinase inhibitors. Searching nature for novel scaffolds is a promising way to find new chemical tools with which we can better understand the development of drug resistance to current targeted therapy and study ways to bypass and overcome such drug resistance.
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