4DED
Aurora A in complex with YL1-038-21
Summary for 4DED
| Entry DOI | 10.2210/pdb4ded/pdb |
| Related | 4DEA 4DEB 4DEE |
| Descriptor | Aurora kinase A, 2-({2-[(4-carbamoylphenyl)amino]pyrimidin-4-yl}amino)benzamide, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | protein kinase, aurora a, dfg-in, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm, cytoskeleton, centrosome: O14965 |
| Total number of polymer chains | 1 |
| Total formula weight | 32893.69 |
| 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 Cited by 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: 22803810DOI: 10.1021/jm300334d PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.05 Å) |
Structure validation
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