4DEB: Aurora A In Complex With Rk2-17-01

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.
PDB ID: 4DEBDownload
MMDB ID: 102162
PDB Deposition Date: 2012/1/20
Updated in MMDB: 2012/09
Experimental Method:
x-ray diffraction
Resolution: 3.05  Å
Source Organism:
Similar Structures:
Biological Unit for 4DEB: monomeric; determined by author and by software (PISA)
Molecular Components in 4DEB
Label Count Molecule
Protein (1 molecule)
Aurora Kinase a(Gene symbol: AURKA)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB