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

  • J Med Chem. 2009 Jan 22;52(2):379-88. doi: 10.1021/jm800984v.
Steven Howard  1 ,  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 Tisi ,  Glyn Williams ,  Mladen Vinković ,  Paul G Wyatt
Affiliations
  • 1. Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. [email protected]
PMID: 19143567 DOI: 10.1021/jm800984v
Abstract

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.

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