3CE3
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with a Pyrrolopyridinepyridone based inhibitor
Summary for 3CE3
| Entry DOI | 10.2210/pdb3ce3/pdb |
| Related | 3C1X |
| Descriptor | Hepatocyte growth factor receptor, 1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (3 entities in total) |
| Functional Keywords | receptor tyrosine kinase, signal transduction, grb2, shc, atp-binding, glycoprotein, membrane, nucleotide-binding, phosphoprotein, proto-oncogene, transferase, transmembrane, tyrosine-protein kinase |
| Biological source | Homo sapiens (human) |
| Cellular location | Membrane; Single-pass type I membrane protein: P08581 |
| Total number of polymer chains | 1 |
| Total formula weight | 35893.45 |
| Authors | Sack, J. (deposition date: 2008-02-28, release date: 2008-08-26, Last modification date: 2024-02-21) |
| Primary citation | Kim, K.S.,Zhang, L.,Schmidt, R.,Cai, Z.W.,Wei, D.,Williams, D.K.,Lombardo, L.J.,Trainor, G.L.,Xie, D.,Zhang, Y.,An, Y.,Sack, J.S.,Tokarski, J.S.,Darienzo, C.,Kamath, A.,Marathe, P.,Zhang, Y.,Lippy, J.,Jeyaseelan, R.,Wautlet, B.,Henley, B.,Gullo-Brown, J.,Manne, V.,Hunt, J.T.,Fargnoli, J.,Borzilleri, R.M. Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities. J.Med.Chem., 51:5330-5341, 2008 Cited by PubMed Abstract: Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model. PubMed: 18690676DOI: 10.1021/jm800476q PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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