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Research Articles: Therapeutics

Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach

¹ College of Pharmacy and ² Arizona Cancer Center, University of Arizona, Tucson, Arizona

Requests for reprints: Laurence H. Hurley, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724. Phone: 520-626-5621; Fax: 520-626-5623. E-mail: hurley{at}pharmacy.arizona.edu

Aurora A and Aurora B are potential targets for anticancer drug development due to their roles in tumorigenesis and disease progression. To identify small-molecule inhibitors of the Aurora kinases, we undertook a structure-based design approach that used three-dimensional structural models of the Aurora A kinase and molecular docking simulations of chemical entities. Based on these computational methods, a new generation of inhibitors derived from quinazoline and pyrimidine-based tricyclic scaffolds were synthesized and evaluated for Aurora A kinase inhibitory activity, which led to the identification of 4-(6,7-dimethoxy-9H-1,3,9-triaza-fluoren-4-yl)-piperazine-1-carbothioic acid [4-(pyrimidin-2-ylsulfamoyl)-phenyl]-amide. The lead compound showed selectivity for the Aurora kinases when it was evaluated against a panel of diverse kinases. Additionally, the compound was evaluated in cell-based assays, showing a dose-dependent decrease in phospho-histone H3 levels and an arrest of the cell cycle in the G₂-M fraction. Although biological effects were observed only at relatively high concentrations, this chemical series provides an excellent starting point for drug optimization and further development. [Mol Cancer Ther 2006;5(7):1764–72]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: S.L. Warner and S. Bashyam contributed equally to this work.

³ http://www.upstate.com/features/kp_protocols.asp

Received 12/14/05; revised 5/ 8/06; accepted 5/16/06.