2P2H

Crystal structure of the VEGFR2 kinase domain in complex with a pyridinyl-triazine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.205 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Evolution of a Highly Selective and Potent 2-(Pyridin-2-yl)-1,3,5-triazine Tie-2 Kinase Inhibitor

Hodous, B.L.Geuns-Meyer, S.D.Hughes, P.E.Albrecht, B.K.Bellon, S.Bready, J.Caenepeel, S.Cee, V.J.Chaffee, S.C.Coxon, A.Emery, M.Fretland, J.Gallant, P.Gu, Y.Hoffman, D.Johnson, R.E.Kendall, R.Kim, J.L.Long, A.M.Morrison, M.Olivieri, P.R.Patel, V.F.Polverino, A.Rose, P.Tempest, P.Wang, L.Whittington, D.A.Zhao, H.

(2007) J Med Chem 50: 611-626

  • DOI: https://doi.org/10.1021/jm061107l
  • Primary Citation of Related Structures:  
    2P2H, 2P2I, 2P4I

  • PubMed Abstract: 

    Inhibition of angiogenesis is a promising and clinically validated approach for limiting tumor growth and survival. The receptor tyrosine kinase Tie-2 is expressed almost exclusively in the vascular endothelium and is required for developmental angiogenesis and vessel maturation. However, the significance of Tie-2 signaling in tumor angiogenesis is not well understood. In order to evaluate the therapeutic utility of inhibiting Tie-2 signaling, we developed a series of potent and orally bioavailable small molecule Tie-2 kinase inhibitors with selectivity over other kinases, especially those that are believed to be important for tumor angiogenesis. Our earlier work provided pyridinyl pyrimidine 6 as a potent, nonselective Tie-2 inhibitor that was designed on the basis of X-ray cocrystal structures of KDR inhibitors 34 (triazine) and 35 (nicotinamide). Lead optimization resulted in pyridinyl triazine 63, which exhibited >30-fold selectivity over a panel of kinases, good oral exposure, and in vivo inhibition of Tie-2 phosphorylation.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139-1581, USA. bhodous@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): 3 
Gene Names: KDRFLK1
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
994
Query on 994

Download Ideal Coordinates CCD File 
B [auth A]4-(2-anilinopyridin-3-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-amine
C23 H22 N6 O3
YRSYWYSGZPRSOP-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
994 Binding MOAD:  2P2H IC50: 68 (nM) from 1 assay(s)
PDBBind:  2P2H IC50: 68 (nM) from 1 assay(s)
BindingDB:  2P2H IC50: 68 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.205 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.595α = 90
b = 136.915β = 90
c = 58.725γ = 90
Software Package:
Software NamePurpose
SCALEPACKdata scaling
EPMRphasing
CNSrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-03-20
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2017-08-16
    Changes: Refinement description, Source and taxonomy
  • Version 1.4: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.5: 2024-02-21
    Changes: Data collection