3F82

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of N-(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a Selective and Orally Efficacious Inhibitor of the Met Kinase Superfamily

Schroeder, G.M.An, Y.Cai, Z.W.Chen, X.T.Clark, C.Cornelius, L.A.Dai, J.Gullo-Brown, J.Gupta, A.Henley, B.Hunt, J.T.Jeyaseelan, R.Kamath, A.Kim, K.Lippy, J.Lombardo, L.J.Manne, V.Oppenheimer, S.Sack, J.S.Schmidt, R.J.Shen, G.Stefanski, K.Tokarski, J.S.Trainor, G.L.Wautlet, B.S.Wei, D.Williams, D.K.Zhang, Y.Zhang, Y.Fargnoli, J.Borzilleri, R.M.

(2009) J Med Chem 52: 1251-1254

  • DOI: https://doi.org/10.1021/jm801586s
  • Primary Citation of Related Structures:  
    3F82

  • PubMed Abstract: 

    Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.


  • Organizational Affiliation

    Bristol-Myers Squibb Research and Development, Princeton, New Jersey, 08543-4000, USA. gretchen.schroeder@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
hepatocyte growth factor receptor314Homo sapiensMutation(s): 3 
Gene Names: MET
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P08581 (Homo sapiens)
Explore P08581 
Go to UniProtKB:  P08581
PHAROS:  P08581
GTEx:  ENSG00000105976 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08581
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
353
Query on 353

Download Ideal Coordinates CCD File 
B [auth A]N-{4-[(2-amino-3-chloropyridin-4-yl)oxy]-3-fluorophenyl}-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
C25 H19 Cl F2 N4 O4
VNBRGSXVFBYQNN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
353 Binding MOAD:  3F82 Ki: 4.6 (nM) from 1 assay(s)
PDBBind:  3F82 Ki: 4.6 (nM) from 1 assay(s)
BindingDB:  3F82 IC50: min: 2.5, max: 214 (nM) from 9 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.180 
  • R-Value Observed: 0.183 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.67α = 90
b = 46.883β = 90
c = 157.65γ = 90
Software Package:
Software NamePurpose
AMoREphasing
BUSTER-TNTrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-03-31 
  • Deposition Author(s): Sack, J.

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-31
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references
  • Version 1.3: 2023-12-27
    Changes: Data collection