2X6D: Aurora-A bound to an inhibitor

Lead optimization studies using 7 as the starting point led to a new class of imidazo[4,5-b]pyridine-based inhibitors of Aurora kinases that possessed the 1-benzylpiperazinyl motif at the 7-position, and displayed favorable in vitro properties. Cocrystallization of Aurora-A with 40c (CCT137444) provided a clear understanding into the interactions of this novel class of inhibitors with the Aurora kinases. Subsequent physicochemical property refinement by the incorporation of solubilizing groups led to the identification of 3-((4-(6-bromo-2-(4-(4-methylpiperazin-1-yl)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)piperazin-1-yl)methyl)-5-methylisoxazole (51, CCT137690) which is a potent inhibitor of Aurora kinases (Aurora-A IC(50) = 0.015 +/- 0.003 muM, Aurora-B IC(50) = 0.025 muM, Aurora-C IC(50) = 0.019 muM). Compound 51 is highly orally bioavailable, and in in vivo efficacy studies it inhibited the growth of SW620 colon carcinoma xenografts following oral administration with no observed toxicities as defined by body weight loss.
PDB ID: 2X6DDownload
MMDB ID: 83151
PDB Deposition Date: 2010/2/17
Updated in MMDB: 2010/07
Experimental Method:
x-ray diffraction
Resolution: 2.796  Å
Source Organism:
Similar Structures:
Biological Unit for 2X6D: monomeric; determined by author and by software (PISA)
Molecular Components in 2X6D
Label Count Molecule
Protein (1 molecule)
Serine/threonine-protein Kinase 6(Gene symbol: AURKA)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB