Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening

详细信息    查看全文

• 作者：Falco Kilchmann ; Maria J. Marcaida ; Sachin Kotak ; Thomas Schick ; Silvan D. Boss ; Mahendra Awale ; Pierre Gönczy ; Jean-Louis Reymond
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 11, 2016
• 年：2016
• 卷：59
• 期：15
• 页码：7188-7211
• 全文大小：1208K
• 年卷期：0
• ISSN：1520-4804

文摘

Here we report the discovery of a selective inhibitor of Aurora A, a key regulator of cell division and potential anticancer target. We used the atom category extended ligand overlap score (xLOS), a 3D ligand-based virtual screening method recently developed in our group, to select 437 shape and pharmacophore analogs of reference kinase inhibitors. Biochemical screening uncovered two inhibitor series with scaffolds unprecedented among kinase inhibitors. One of them was successfully optimized by structure-based design to a potent Aurora A inhibitor (IC₅₀ = 2 nM) with very high kinome selectivity for Aurora kinases. This inhibitor locks Aurora A in an inactive conformation and disrupts binding to its activator protein TPX2, which impairs Aurora A localization at the mitotic spindle and induces cell division defects. This phenotype can be rescued by inhibitor-resistant Aurora A mutants. The inhibitor furthermore does not induce Aurora B specific effects in cells.