Fragment-based discovery of the pyrazol-4-yl urea (AT9283), a multitargeted kinase inhibitor with potent aurora kinase activity

Steven Howard (Lead / Corresponding author), Valerio Berdini, John A Boulstridge, Maria G Carr, David M Cross, Jayne Curry, Lindsay A Devine, Theresa R Early, Lynsey Fazal, Adrian L Gill, Michelle Heathcote, Sarita Maman, Julia E Matthews, Rachel L McMenamin, Eva F Navarro, Michael A O'Brien, Marc O'Reilly, David C Rees, Matthias Reule, Dominic TisiGlyn Williams, Mladen Vinković, Paul G Wyatt

    Research output: Contribution to journalArticlepeer-review

    310 Citations (Scopus)


    Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.
    Original languageEnglish
    Pages (from-to)379-88
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Issue number2
    Publication statusPublished - 2009


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