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Discovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

dc.creatorWang, S.en
dc.creatorMidgley, C. A.en
dc.creatorScaërou, F.en
dc.creatorGrabarek, J. B.en
dc.creatorGriffiths, G.en
dc.creatorJackson, W.en
dc.creatorKontopidis, G.en
dc.creatorMcClue, S. J.en
dc.creatorMcInnes, C.en
dc.creatorMeades, C.en
dc.creatorMezna, M.en
dc.creatorPlater, A.en
dc.creatorStuart, I.en
dc.creatorThomas, M. P.en
dc.creatorWood, G.en
dc.creatorClarke, R. G.en
dc.creatorBlake, D. G.en
dc.creatorZheleva, D. I.en
dc.creatorLane, D. P.en
dc.creatorJackson, R. C.en
dc.creatorGlover, D. M.en
dc.creatorFischer, P. M.en
dc.date.accessioned2015-11-23T10:54:09Z
dc.date.available2015-11-23T10:54:09Z
dc.date.issued2010
dc.identifier10.1021/jm901913s
dc.identifier.issn222623
dc.identifier.urihttp://hdl.handle.net/11615/34663
dc.description.abstractThrough 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- morpholinophenylamino)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. © 2010 American Chemical Society.en
dc.source.urihttp://www.scopus.com/inward/record.url?eid=2-s2.0-77953221993&partnerID=40&md5=db1b122af10be624094a386209438c24
dc.subject1 n [4 (2,4 dimethylthiazol 5 yl)pyrimidin 2 yl] n',n' dimethylbenzene 1,4 diamineen
dc.subject4 methyl 5 [2 (4 morpholinophenylamino)pyrimidin 4 yl]thiazol 2 amineen
dc.subjectaurora A kinaseen
dc.subjectaurora B kinaseen
dc.subjectaurora kinase inhibitoren
dc.subjectcytotoxic agenten
dc.subjecthistone H3en
dc.subjectn phenyl 4 (thiazol 5 yl)pyrimidin 2 amineen
dc.subjectunclassified drugen
dc.subjectanimal experimenten
dc.subjectantineoplastic activityen
dc.subjectarea under the curveen
dc.subjectarticleen
dc.subjectcancer cell cultureen
dc.subjectcell deathen
dc.subjectcontrolled studyen
dc.subjectcorrelation analysisen
dc.subjectdissociation constanten
dc.subjectdrug bioavailabilityen
dc.subjectdrug eliminationen
dc.subjectdrug identificationen
dc.subjectdrug potencyen
dc.subjectdrug selectivityen
dc.subjectdrug solubilityen
dc.subjectdrug structureen
dc.subjectenzyme inhibitionen
dc.subjecthumanen
dc.subjecthuman tissueen
dc.subjectintestine mucosa permeabilityen
dc.subjectmaximum plasma concentrationen
dc.subjectmitosisen
dc.subjectmouseen
dc.subjectnonhumanen
dc.subjectpartition coefficienten
dc.subjectphenotypeen
dc.subjectpolyploidyen
dc.subjectprotein phosphorylationen
dc.subjectAdenosine Triphosphateen
dc.subjectAnimalsen
dc.subjectBinding, Competitiveen
dc.subjectCell Line, Tumoren
dc.subjectCell Proliferationen
dc.subjectDrug Discoveryen
dc.subjectHumansen
dc.subjectInhibitory Concentration 50en
dc.subjectMiceen
dc.subjectModels, Molecularen
dc.subjectProtein Conformationen
dc.subjectProtein Kinase Inhibitorsen
dc.subjectProtein-Serine-Threonine Kinasesen
dc.subjectPyrimidinesen
dc.subjectSubstrate Specificityen
dc.subjectThiazolesen
dc.subjectXenograft Model Antitumor Assaysen
dc.titleDiscovery of N-Phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitorsen
dc.typejournalArticleen


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