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

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

Affiliation

  • 1 Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, UK. s.howard@astex-therapeutics.com
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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