Fragment-Based Discovery of the Pyrazol-4-yl Urea (AT9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity
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- 作者：Steven Howard ; 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 ; Ju
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：January 22, 2009
- 年：2009
- 卷：52
- 期：2
- 页码：379-388
- 全文大小：310K
- 年卷期：v.52,no.2(January 22, 2009)
- ISSN：1520-4804
文摘
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 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.