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

…, L Fazal, AL Gill, M Heathcote, S Maman…

文献索引：Howard, Steven; Berdini, Valerio; Boulstridge, John A.; Carr, Maria G.; Cross, David M.; Curry, Jayne; Devine, Lindsay A.; Early, Theresa R.; Fazal, Lynsey; Gill, Adrian L.; Heathcote, Michelle; Maman, Sarita; Matthews, Julia E.; McMenamin, Rachel L.; Navarro, Eva F.; O'Brien, Michael A.; O'Reilly, Marc; Rees, David C.; Reule, Matthias; Tisi, Dominic; Williams, Glyn; Vinkovic, Mladen; Wyatt, Paul G. Journal of Medicinal Chemistry, 2009 , vol. 52, # 2 p. 379 - 388

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被引用次数: 231

摘要

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 (IC50≈ 3 nM) dual Aurora ...