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

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Howard S, Berdini V, Boulstridge JA, Carr MG, Cross DM, Curry J, Devine LA, Early TR, Fazal L, Gill AL, Heathcote M, Maman S, Matthews JE, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Rees DC, Reule M, Tisi D, Williams G, Vinkovic M, Wyatt PG

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.

PubMed ID
19143567 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
2-(1H-pyrazol-3-yl)-1H-benzimidazoleAurora kinase AIC 50 (nM)910722Details
N-[3-(1H-BENZIMIDAZOL-2-YL)-1H-PYRAZOL-4-YL]BENZAMIDEAurora kinase AIC 50 (nM)5.9722Details
N-[3-(1H-BENZIMIDAZOL-2-YL)-1H-PYRAZOL-4-YL]BENZAMIDECyclin-dependent kinase 2IC 50 (nM)527.222Details