title: Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR Chemical Biology and NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Falco
authors.initials: F
authors.lastname: Kilchmann
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR Chemical Biology and NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Marcaida
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, National Center of Competence in Research NCCR Chemical Biology, Swiss Federal Institute of Technology (EPFL) , CH-1015 Lausanne, Switzerland.
authors.forename: Sachin
authors.initials: S
authors.lastname: Kotak
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR Chemical Biology and NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schick
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR Chemical Biology and NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Silvan D
authors.initials: SD
authors.lastname: Boss
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR Chemical Biology and NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Awale
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, National Center of Competence in Research NCCR Chemical Biology, Swiss Federal Institute of Technology (EPFL) , CH-1015 Lausanne, Switzerland.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gönczy
authors.affiliation: Department of Chemistry and Biochemistry, National Center of Competence in Research NCCR Chemical Biology and NCCR TransCure, University of Berne , Freiestrasse 3, 3012 Berne, Switzerland.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Reymond
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D064096:Aurora Kinase A