2W1F
Structure determination of Aurora Kinase in complex with inhibitor
Summary for 2W1F
Entry DOI | 10.2210/pdb2w1f/pdb |
Related | 1MQ4 1MUO 1OL5 1OL6 1OL7 2BMC 2C6D 2C6E 2J4Z 2J50 2W1C 2W1D 2W1E 2W1G 2W1H 2W1I |
Descriptor | SERINE/THREONINE-PROTEIN KINASE 6, N-[3-(1H-BENZIMIDAZOL-2-YL)-1H-PYRAZOL-4-YL]BENZAMIDE (3 entities in total) |
Functional Keywords | cancer, aurora, kinase, inhibitor, nucleotide-binding, serine/threonine-protein kinase, transferase, atp-binding, polymorphism, phosphoprotein, cell cycle |
Biological source | HOMO SAPIENS (HUMAN) |
Total number of polymer chains | 1 |
Total formula weight | 32461.26 |
Authors | Howard, S.,Berdini, V.,Boulstridge, J.A.,Carr, M.G.,Cross, D.M.,Curry, J.,Devine, L.A.,Early, T.R.,Fazal, L.,Gill, A.L.,Heathcote, M.,Maman, S.,Matthews, J.E.,McMenamin, R.L.,Navarro, E.F.,O'Brien, M.A.,O'Reilly, M.,Rees, D.C.,Reule, M.,Tisi, D.,Williams, G.,Vinkovic, M.,Wyatt, P.G. (deposition date: 2008-10-17, release date: 2009-01-27, Last modification date: 2024-05-08) |
Primary citation | Howard, S.,Berdini, V.,Boulstridge, J.A.,Carr, M.G.,Cross, D.M.,Curry, J.,Devine, L.A.,Early, T.R.,Fazal, L.,Gill, A.L.,Heathcote, M.,Maman, S.,Matthews, J.E.,Mcmenamin, R.L.,Navarro, E.F.,O'Brien, M.A.,O'Reilly, M.,Rees, D.C.,Reule, M.,Tisi, D.,Williams, G.,Vinkovic, M.,Wyatt, P.G. Fragment-Based Discovery of the Pyrazol-4-Yl Urea (at9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity. J.Med.Chem., 52:379-, 2009 Cited by PubMed Abstract: Here, we describe the identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment. Aurora kinases play a key role in the regulation of mitosis and in recent years have become attractive targets for the treatment of cancer. X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimization toward potent (IC(50) approximately 3 nM) dual Aurora A/Aurora B inhibitors. These compounds inhibited growth and survival of HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora B kinase inhibition. Optimization of cellular activity and physicochemical properties ultimately led to the identification of compound 16 (AT9283). In addition to Aurora A and Aurora B, compound 16 was also found to inhibit a number of other kinases including JAK2 and Abl (T315I). This compound demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials. PubMed: 19143567DOI: 10.1021/JM800984V PDB entries with the same primary citation |
Experimental method | X-RAY DIFFRACTION (2.85 Å) |
Structure validation
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