3c1x: Difference between revisions
New page: left|200px {{Structure |PDB= 3c1x |SIZE=350|CAPTION= <scene name='initialview01'>3c1x</scene>, resolution 2.17Å |SITE= <scene name='pdbsite=AC1:Ckk+Binding+Site+... |
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|PDB= 3c1x |SIZE=350|CAPTION= <scene name='initialview01'>3c1x</scene>, resolution 2.17Å | |PDB= 3c1x |SIZE=350|CAPTION= <scene name='initialview01'>3c1x</scene>, resolution 2.17Å | ||
|SITE= <scene name='pdbsite=AC1:Ckk+Binding+Site+For+Residue+A+1500'>AC1</scene> | |SITE= <scene name='pdbsite=AC1:Ckk+Binding+Site+For+Residue+A+1500'>AC1</scene> | ||
|LIGAND= <scene name='pdbligand=CKK:'>CKK</scene> | |LIGAND= <scene name='pdbligand=CKK:N-{[4-({5-[(4-AMINOPIPERIDIN-1-YL)METHYL]PYRROLO[2,1-F][1,2,4]TRIAZIN-4-YL}OXY)-3-FLUOROPHENYL]CARBAMOYL}-2-(4-FLUOROPHENYL)ACETAMIDE'>CKK</scene> | ||
|ACTIVITY= [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] | |ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span> | ||
|GENE= MET ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |GENE= MET ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | ||
|DOMAIN= | |||
|RELATEDENTRY= | |||
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3c1x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3c1x OCA], [http://www.ebi.ac.uk/pdbsum/3c1x PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=3c1x RCSB]</span> | |||
}} | }} | ||
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==Overview== | ==Overview== | ||
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner. | An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner. | ||
==Disease== | |||
Known disease associated with this structure: Hepatocellular carcinoma, childhood type OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164860 164860]], Renal cell carcinoma, papillary, familial and sporadic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164860 164860]], Autism, suseptibility to, 9 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=164860 164860]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Sack, J.]] | [[Category: Sack, J.]] | ||
[[Category: atp-binding]] | [[Category: atp-binding]] | ||
[[Category: glycoprotein]] | [[Category: glycoprotein]] | ||
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[[Category: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 05:30:16 2008'' | ||
Revision as of 05:30, 31 March 2008
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| , resolution 2.17Å | |||||||
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| Sites: | |||||||
| Ligands: | |||||||
| Gene: | MET (Homo sapiens) | ||||||
| Activity: | Receptor protein-tyrosine kinase, with EC number 2.7.10.1 | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor c-MET in complex with a Pyrrolotriazine based inhibitor
OverviewOverview
An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.
DiseaseDisease
Known disease associated with this structure: Hepatocellular carcinoma, childhood type OMIM:[164860], Renal cell carcinoma, papillary, familial and sporadic OMIM:[164860], Autism, suseptibility to, 9 OMIM:[164860]
About this StructureAbout this Structure
3C1X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase., Schroeder GM, Chen XT, Williams DK, Nirschl DS, Cai ZW, Wei D, Tokarski JS, An Y, Sack J, Chen Z, Huynh T, Vaccaro W, Poss M, Wautlet B, Gullo-Brown J, Kellar K, Manne V, Hunt JT, Wong TW, Lombardo LJ, Fargnoli J, Borzilleri RM, Bioorg Med Chem Lett. 2008 Mar 15;18(6):1945-51. Epub 2008 Feb 7. PMID:18289854
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