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Lookup NU author(s): Professor Steve Wedge
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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.
Author(s): Mortlock AA, Foote KM, Heron NM, Jung FH, Pasquet G, Lohmann JJ, Warin N, Renaud F, DeSavi C, Roberts NJ, Johnson T, Dousson CB, Hill GB, Perkins D, Hatter G, Wilkinson RW, Wedge SR, Heaton SP, Odedra R, Keen NJ, Crafter C, Brown E, Thompson K, Brightwell S, Khatri L, Brady MC, Kearney S, McKillop D, Rhead S, Parry T, Green S
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
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