3O50
Crystal structure of benzamide 9 bound to AuroraA
Summary for 3O50
| Entry DOI | 10.2210/pdb3o50/pdb |
| Related | 3O51 |
| Descriptor | cDNA FLJ58295, highly similar to Serine/threonine-protein kinase 6, N-{3-methyl-4-[(3-pyrimidin-4-ylpyridin-2-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (3 entities in total) |
| Functional Keywords | auroraa, kinase domain, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 62974.22 |
| Authors | Huang, X. (deposition date: 2010-07-27, release date: 2010-08-18, Last modification date: 2024-02-21) |
| Primary citation | Cee, V.J.,Schenkel, L.B.,Hodous, B.L.,Deak, H.L.,Nguyen, H.N.,Olivieri, P.R.,Romero, K.,Bak, A.,Be, X.,Bellon, S.,Bush, T.L.,Cheng, A.C.,Chung, G.,Coats, S.,Eden, P.M.,Hanestad, K.,Gallant, P.L.,Gu, Y.,Huang, X.,Kendall, R.L.,Lin, M.H.,Morrison, M.J.,Patel, V.F.,Radinsky, R.,Rose, P.E.,Ross, S.,Sun, J.R.,Tang, J.,Zhao, H.,Payton, M.,Geuns-Meyer, S.D. Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor. J.Med.Chem., 53:6368-6377, 2010 Cited by PubMed Abstract: The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h. PubMed: 20684549DOI: 10.1021/jm100394y PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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