4ZS0

Human Aurora A catalytic domain bound to SB-6-OH

Summary for 4ZS0

• Entry DOI: 10.2210/pdb4zs0/pdb
• Descriptor: Aurora kinase A, 5-hydroxy-1'H-1,2'-bibenzimidazol-2(3H)-one (2 entities in total)
• Functional Keywords: aurora, kinase, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965
• Total number of polymer chains: 1
• Total formula weight: 33215.04

Authors

Marcaida, M.J.,Kilchmann, F.,Schick, T.,Reymond, J.L. (deposition date: 2015-05-12, release date: 2016-07-20, Last modification date: 2024-01-10)

Primary citation

Kilchmann, F.,Marcaida, M.J.,Kotak, S.,Schick, T.,Boss, S.D.,Awale, M.,Gonczy, P.,Reymond, J.L.
Discovery of a Selective Aurora A Kinase Inhibitor by Virtual Screening.
J.Med.Chem., 59:7188-7211, 2016

PubMed 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.

PubMed: 27391133
DOI: 10.1021/acs.jmedchem.6b00709

Experimental method

X-RAY DIFFRACTION (3 Å)