3U6J

Crystal structure of the VEGFR2 kinase domain in complex with a pyrazolone inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design of novel class II c-Met inhibitors: 1. Identification of pyrazolone-based derivatives.

Norman, M.H.Liu, L.Lee, M.Xi, N.Fellows, I.D'Angelo, N.D.Dominguez, C.Rex, K.Bellon, S.F.Kim, T.S.Dussault, I.

(2012) J Med Chem 55: 1858-1867

  • DOI: https://doi.org/10.1021/jm201330u
  • Primary Citation of Related Structures:  
    3U6H, 3U6I, 3U6J

  • PubMed Abstract: 

    Deregulation of c-Met receptor tyrosine kinase activity leads to tumorigenesis and metastasis in animal models. More importantly, the identification of activating mutations in c-Met, as well as MET gene amplification in human cancers, points to c-Met as an important target for cancer therapy. We have previously described two classes of c-Met kinase inhibitors (class I and class II) that differ in their binding modes and selectivity profiles. The class II inhibitors tend to have activities on multiple kinases. Knowledge of the binding mode of these molecules in the c-Met protein led to the design and evaluation of several new class II c-Met inhibitors that utilize various 5-membered cyclic carboxamides to conformationally restrain key pharmacophoric groups within the molecule. These investigations resulted in the identification of a potent and novel class of pyrazolone c-Met inhibitors with good in vivo activity.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. markn@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vascular endothelial growth factor receptor 2314Homo sapiensMutation(s): 2 
Gene Names: FLK1KDR
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P35968 (Homo sapiens)
Explore P35968 
Go to UniProtKB:  P35968
PHAROS:  P35968
GTEx:  ENSG00000128052 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP35968
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
03X
Query on 03X

Download Ideal Coordinates CCD File 
B [auth A]N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]-3-fluorophenyl}-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
C29 H25 F N4 O5
SBLMCLDRWJNEJK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
03X PDBBind:  3U6J IC50: 6.2 (nM) from 1 assay(s)
BindingDB:  3U6J IC50: min: 7.8, max: 10 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.194α = 90
b = 65.268β = 117.94
c = 57.323γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
DENZOdata reduction
EPMRphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-22
    Type: Initial release
  • Version 1.1: 2012-05-23
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations