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

Shudong Wang, Carol A. Midgley, Frederic Scaërou, Joanna B. Grabarek, Gary Griffiths, Wayne Jackson, George Kontopidis, Steven J. McClue, Campbell McInnes, Christopher Meades, Mokdad Mezna, Andy Plater, Iain Stuart, Mark P. Thomas, Gavin Wood, Rosemary G. Clarke, David G. Blake, Daniella I. Zheleva, David P. Lane, Robert C. JacksonDavid M. Glover, P.M. Fischer

    Research output: Contribution to journalArticlepeer-review

    81 Citations (Scopus)


    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- morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K 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.
    Original languageEnglish
    Pages (from-to)4367-4378
    Number of pages12
    JournalJournal of Medicinal Chemistry
    Issue number11
    Early online date12 May 2010
    Publication statusPublished - 10 Jun 2010


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