4DEE

Aurora A in complex with ADP

Summary for 4DEE

• Entry DOI: 10.2210/pdb4dee/pdb
• Related: 4DEA 4DEB 4DED
• Descriptor: Aurora kinase A, MAGNESIUM ION, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: protein kinase, aurora a, dfg-in, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965
• Total number of polymer chains: 1
• Total formula weight: 32834.93

Authors

Martin, M.P.,Zhu, J.-Y.,Schonbrunn, E. (deposition date: 2012-01-20, release date: 2012-08-22, Last modification date: 2023-09-13)

Primary citation

Lawrence, H.R.,Martin, M.P.,Luo, Y.,Pireddu, R.,Yang, H.,Gevariya, H.,Ozcan, S.,Zhu, J.Y.,Kendig, R.,Rodriguez, M.,Elias, R.,Cheng, J.Q.,Sebti, S.M.,Schonbrunn, E.,Lawrence, N.J.
Development of o-Chlorophenyl Substituted Pyrimidines as Exceptionally Potent Aurora Kinase Inhibitors.
J.Med.Chem., 55:7392-7416, 2012

PubMed Abstract: The o-carboxylic acid substituted bisanilinopyrimidine 1 was identified as a potent hit (Aurora A IC(50) = 6.1 ± 1.0 nM) from in-house screening. Detailed structure-activity relationship (SAR) studies indicated that polar substituents at the para position of the B-ring are critical for potent activity. X-ray crystallography studies revealed that compound 1 is a type I inhibitor that binds the Aurora kinase active site in a DFG-in conformation. Structure-activity guided replacement of the A-ring carboxylic acid with halogens and incorporation of fluorine at the pyrimidine 5-position led to highly potent inhibitors of Aurora A that bind in a DFG-out conformation. B-Ring modifications were undertaken to improve the solubility and cell permeability. Compounds such as 9m with water-solubilizing moieties at the para position of the B-ring inhibited the autophosphorylation of Aurora A in MDA-MB-468 breast cancer cells.

PubMed: 22803810
DOI: 10.1021/jm300334d

Experimental method

X-RAY DIFFRACTION (2.3 Å)