Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening

Kilchmann, Falco; Marcaida, Maria; Sachin, Kotak; Schick, Thomas; Boss, Silvan; Awale, Mahendra; Gönczy, Pierre; Reymond, Jean-Louis (2016). Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening. Journal of medicinal chemistry, 59(15), pp. 7188-7211. American Chemical Society 10.1021/acs.jmedchem.6b00709

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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 (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Kilchmann, Falco; Marcaida, Maria; Schick, Thomas; Awale, Mahendra and Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0022-2623

Publisher:

American Chemical Society

Language:

English

Submitter:

Thomas Schick

Date Deposited:

27 Jul 2017 08:47

Last Modified:

27 Jul 2017 08:47

Publisher DOI:

10.1021/acs.jmedchem.6b00709

BORIS DOI:

10.7892/boris.101461

URI:

https://boris.unibe.ch/id/eprint/101461

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