期刊
LIFE-BASEL
卷 12, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/life12060876
关键词
quinazoline; Aurora A; kinases; anticancer; molecular docking; cell cycle; apoptosis
资金
- KIST Institutional programs from the Korea Institute of Science and Technology [2E31624]
- Creative Fusion Research Program through the Creative Allied Project - National Research Council of Science Technology [CAP-12-1-KIST]
New quinazoline derivatives were designed with enhanced selectivity toward Aurora A. Compound 6e showed significant potency and selectivity, and further assays confirmed its potential as a lead compound for selective inhibition of Aurora A kinase with apoptosis properties.
New quinazoline derivatives were designed based on the structural modification of the reported inhibitors to enhance their selectivity toward Aurora A. The synthesized compounds were tested over Aurora A, and a cytotoxicity assay was performed over NCI cell lines to select the best candidate for further evaluation. Compound 6e (2-(3-bromophenyl)-8-fluoroquinazoline-4-carboxylic acid) was the most potent compound among the tested derivatives. A Kinase panel assay was conducted for compound 6e over 14 kinases to evaluate its selectivity profile. Further cell cycle and apoptosis analysis were evaluated for compound 6e over the MCF-7 cell line at its IC50 of 168.78 mu M. It arrested the cell cycle at the G1 phase and induced apoptosis. Molecular docking was performed to explore the possible binding mode of compound 6e into the active site. It showed significant binding into the main pocket in addition to potential binding interactions with the key amino acid residues. Accordingly, compound 6e can be considered a potential lead for further structural and molecular optimization of the quinazoline-based carboxylic acid scaffold for Aurora A kinase selective inhibition with apoptosis properties.
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