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Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine Aurora Kinase Inhibitors

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. (2010). Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine Aurora Kinase Inhibitors. Journal of Medicinal Chemistry, 53(11) pp. 4367–4378.

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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
ISSN: 0022-2623
Academic Unit/Department: 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)
Item ID: 21728
Depositing User: Astrid Peterkin
Date Deposited: 10 Jun 2010 11:41
Last Modified: 12 Oct 2016 23:38
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