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Discovery, Synthesis, and in Vivo Activity of a New Class of Pyrazoloquinazolines as Selective Inhibitors of Aurora B Kinase

2007; American Chemical Society; Volume: 50; Issue: 9 Linguagem: Inglês

10.1021/jm061335f

1520-4804

Andrew Mortlock, Kevin M. Foote, Nicola M. Heron, Frédéric Jung, Georges Pasquet, Jean-Jacques M. Lohmann, Nicolas Warin, Fabrice Renaud, Chris De Savi, Nicola Roberts, Trevor Johnson, Cyril B. Dousson, George B. Hill, David Perkins, Glenn Hatter, Robert W. Wilkinson, Stephen R. Wedge, Simon P. Heaton, Rajesh Odedra, Nicholas Keen, Claire Crafter, Elaine Brown, Katherine V. Thompson, Stephen Brightwell, Liz Khatri, Madeleine C. Brady, Sarah Kearney, David McKillop, Steve Rhead, T. Parry, Stephen Green,

Protein Degradation and Inhibitors

The Aurora kinases have been the subject of considerable interest as targets for the development of new anticancer agents. While evidence suggests inhibition of Aurora B kinase gives rise to the more pronounced antiproliferative phenotype, the most clinically advanced agents reported to date typically inhibit both Aurora A and B. We have discovered a series of pyrazoloquinazolines, some of which show greater than 1000-fold selectivity for Aurora B over Aurora A kinase activity, in recombinant enzyme assays. These compounds have been designed for parenteral administration and achieve high levels of solubility by virtue of their ability to be delivered as readily activated phosphate derivatives. The prodrugs are comprehensively converted to the des-phosphate form in vivo, and the active species have advantageous pharmacokinetic properties and safety pharmacology profiles. The compounds display striking in vivo activity, and compound 5 (AZD1152) has been selected for clinical evaluation and is currently in phase 1 clinical trials.