Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies

Title
Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies
Authors
Ahmed Mahammed Elkamhawy박정은조남철심태보배애님노은주
Keywords
CYP450; DDR1 kinase inhibitor; kinase panel; molecular docking; NCI panel
Issue Date
2015-09
Publisher
Journal of enzyme inhibition and medicinal chemistry
Citation
VOL 게재예정, 게재예정
Abstract
Herein, we report compound KST9046, a new agent possessing quinazoline-urea scaffold. Preliminary biological evaluation done by the National Cancer Institute (NCI), USA, showed a great inhibitory effect of KST9046 over the 60 cell-line tumor panel. Accordingly, it was selected for a dose-response assay; a broad spectrum antiproliferative activity with GI50 ranging from 1.3 to 3.9 mM was exerted. To explore a potential kinase inhibitory effect, KST9046 was applied at a single dose of 10 mM against a kinase panel of 347 different enzymes representing 450% of the predicted human protein kinome. Interestingly, selective inhibition of 76% was observed on DDR1 kinase. Further, KST9046 showed an IC50 value of 4.38 mM for DDR1. A molecular docking model presented KST9046 as a potential type III inhibitor for DDR1 kinase with an allosteric mode of interaction, which may offer an explanation for its selectivity. As further investigation, CYP450 assay was carried out for KST9046, it showed a promising toxicity profile against four different isoforms. Based on these findings, KST9046 can be further evaluated as a promising safe new hit for the development of broad spectrum anticancer agents with a selectivity for DDR1 kinase.
URI
http://pubs.kist.re.kr/handle/201004/50469
ISSN
14756366
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KIST Publication > Article
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