3CE3

Crystal structure of the tyrosine kinase domain of the hepatocyte growth factor receptor C-MET in complex with a Pyrrolopyridinepyridone based inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.

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.

(2008) J Med Chem 51: 5330-5341

  • DOI: https://doi.org/10.1021/jm800476q
  • Primary Citation of Related Structures:  
    3CE3

  • 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.


  • Organizational Affiliation

    Department of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research & Development, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. kyoung.kim@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptor314Homo sapiensMutation(s): 4 
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
1FN
Query on 1FN

Download Ideal Coordinates CCD File 
B [auth A]1-(4-fluorophenyl)-N-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide
C25 H16 F2 N4 O3
OBSFXHDOLBYWRJ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1FN Binding MOAD:  3CE3 IC50: 1.8 (nM) from 1 assay(s)
BindingDB:  3CE3 IC50: min: 1.8, max: 5.7 (nM) from 2 assay(s)
PDBBind:  3CE3 IC50: 1.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.275 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.04α = 90
b = 49.137β = 90
c = 159.324γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2008-08-26 
  • Deposition Author(s): Sack, J.

Revision History  (Full details and data files)

  • Version 1.0: 2008-08-26
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2024-02-21
    Changes: Data collection