Wang, Shudong; Midgley, Carol A.; Scaërou, Frederic; Grabarek, Joanna B.; Griffiths, Gary; Jackson, Wayne; Kontopidis, George; McClue, Steven J.; McInnes, Campbell; Meades, Christopher; Mezna, Mokdad; Plater, Andy; Stuart, Iain; Thomas, Mark P.; Wood, Gavin; Clarke, Rosemary G.; Blake, David G.; Zheleva, Daniella I.; Lane, David P.; Jackson, Robert C.; Glover, David M. and Fischer, Peter M.
Due to copyright restrictions, this file is not available for public download
Click here to request a copy from the OU Author.
PDF (Accepted Manuscript)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
|DOI (Digital Object Identifier) Link:||https://doi.org/10.1021/jm901913s|
|Google Scholar:||Look up in Google Scholar|
Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of aurora A and B kinases. It was shown that potency and selectivity of aurora kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenyl-amino)pyrimidin-4-yl)thiazol-2-amine (18; Ki values of 8.0 and 9.2 nM for aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed anticancer activity. Compound 18 (CYC116) is currently undergoing phase-I clinical evaluation in cancer patients.
|Item Type:||Journal Article|
|Copyright Holders:||2010 American Chemical Society|
|Academic Unit/School:||Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
|Interdisciplinary Research Centre:||Biomedical Research Network (BRN)|
|Depositing User:||Astrid Peterkin|
|Date Deposited:||10 Jun 2010 11:41|
|Last Modified:||30 Nov 2016 10:39|
|Share this page:|
Download history for this item
These details should be considered as only a guide to the number of downloads performed manually. Algorithmic methods have been applied in an attempt to remove automated downloads from the displayed statistics but no guarantee can be made as to the accuracy of the figures.