3I5N
Crystal structure of c-Met with triazolopyridazine inhibitor 13
Summary for 3I5N
| Entry DOI | 10.2210/pdb3i5n/pdb |
| Related | 3CD8 |
| Descriptor | Hepatocyte growth factor receptor, 7-methoxy-N-[(6-phenyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl]-1,5-naphthyridin-4-amine (3 entities in total) |
| Functional Keywords | proto-oncogene, rtk, receptor tyrosine kinase, scatter factor receptor, hgf/sf, alternative splicing, atp-binding, chromosomal rearrangement, disease mutation, disulfide bond, glycoprotein, kinase, membrane, nucleotide-binding, phosphoprotein, polymorphism, receptor, 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 | 35599.12 |
| Authors | Bellon, S.F.,Whittington, D.A.,Long, A.M.,Boezio, A.A. (deposition date: 2009-07-06, release date: 2010-01-12, Last modification date: 2023-09-06) |
| Primary citation | Boezio, A.A.,Berry, L.,Albrecht, B.K.,Bauer, D.,Bellon, S.F.,Bode, C.,Chen, A.,Choquette, D.,Dussault, I.,Hirai, S.,Kaplan-Lefko, P.,Larrow, J.F.,Lin, M.H.,Lohman, J.,Potashman, M.H.,Rex, K.,Santostefano, M.,Shah, K.,Shimanovich, R.,Springer, S.K.,Teffera, Y.,Yang, Y.,Zhang, Y.,Harmange, J.C. Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors Bioorg.Med.Chem.Lett., 19:6307-6312, 2009 Cited by PubMed Abstract: Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model. PubMed: 19819693DOI: 10.1016/j.bmcl.2009.09.096 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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