3M11
Crystal Structure of Aurora A Kinase complexed with inhibitor
Summary for 3M11
| Entry DOI | 10.2210/pdb3m11/pdb |
| Descriptor | Serine/threonine-protein kinase 6, 1-(4-{2-[(5,6-diphenylfuro[2,3-d]pyrimidin-4-yl)amino]ethyl}phenyl)-3-phenylurea (3 entities in total) |
| Functional Keywords | aurora kinase inhibitor, x-ray co-crystal analysis, structure-based drug design, atp-binding, cell cycle, cytoskeleton, kinase, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm, cytoskeleton, microtubule organizing center, centrosome : O14965 |
| Total number of polymer chains | 1 |
| Total formula weight | 32884.72 |
| Authors | Wu, J.S.,Leou, J.S.,Coumar, M.S.,Hsieh, H.P.,Wu, S.Y. (deposition date: 2010-03-03, release date: 2011-03-09, Last modification date: 2023-11-01) |
| Primary citation | Coumar, M.S.,Chu, C.Y.,Lin, C.W.,Shiao, H.Y.,Ho, Y.L.,Reddy, R.,Lin, W.H.,Chen, C.H.,Peng, Y.H.,Leou, J.S.,Lien, T.W.,Huang, C.T.,Fang, M.Y.,Wu, S.H.,Wu, J.S.,Chittimalla, S.K.,Song, J.S.,Hsu, J.T.,Wu, S.Y.,Liao, C.C.,Chao, Y.S.,Hsieh, H.P. Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification J.Med.Chem., 53:4980-4988, 2010 Cited by PubMed Abstract: A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases. PubMed: 20550212DOI: 10.1021/jm1000198 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.75 Å) |
Structure validation
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