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Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening

Kilchmann, Falco and Marcaida, Maria J and Kotak, Sachin and Schick, Thomas and Boss, Silvan D and Awale, Mahendra and Gonczy, Pierre and Reymond, Jean-Louis (2016) Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening. In: JOURNAL OF MEDICINAL CHEMISTRY, 59 (15). pp. 7188-7211.

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Official URL: http://dx.doi.org/10.1021/acs.jmedchem.6b00709


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.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, DC 20036 USA
Department/Centre: Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited: 22 Oct 2016 07:26
Last Modified: 22 Oct 2016 07:26
URI: http://eprints.iisc.ac.in/id/eprint/54938

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