3C7Q

Structure of VEGFR2 kinase domain in complex with BIBF1120


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.221 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy.

Hilberg, F.Roth, G.J.Krssak, M.Kautschitsch, S.Sommergruber, W.Tontsch-Grunt, U.Garin-Chesa, P.Bader, G.Zoephel, A.Quant, J.Heckel, A.Rettig, W.J.

(2008) Cancer Res 68: 4774-4782

  • DOI: https://doi.org/10.1158/0008-5472.CAN-07-6307
  • Primary Citation of Related Structures:  
    3C7Q

  • PubMed Abstract: 

    Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a novel treatment modality in oncology. Preclinical findings suggest that long-term clinical outcomes may improve with blockade of additional proangiogenic receptor tyrosine kinases: platelet-derived growth factor receptors (PDGFR) and fibroblast growth factor receptors (FGFR). BIBF 1120 is an indolinone derivative potently blocking VEGF receptor (VEGFR), PDGFR and FGFR kinase activity in enzymatic assays (IC(50), 20-100 nmol/L). BIBF 1120 inhibits mitogen-activated protein kinase and Akt signaling pathways in three cell types contributing to angiogenesis, endothelial cells, pericytes, and smooth muscle cells, resulting in inhibition of cell proliferation (EC(50), 10-80 nmol/L) and apoptosis. In all tumor models tested thus far, including human tumor xenografts growing in nude mice and a syngeneic rat tumor model, BIBF 1120 is highly active at well-tolerated doses (25-100 mg/kg daily p.o.), as measured by magnetic resonance imaging of tumor perfusion after 3 days, reducing vessel density and vessel integrity after 5 days, and inducing profound growth inhibition. A distinct pharmacodynamic feature of BIBF 1120 in cell culture is sustained pathway inhibition (up to 32 hours after 1-hour treatment), suggesting slow receptor off-kinetics. Although BIBF 1120 is rapidly metabolized in vivo by methylester cleavage, resulting in a short mean residence time, once daily oral dosing is fully efficacious in xenograft models. These distinctive pharmacokinetic and pharmacodynamic properties may help explain clinical observations with BIBF 1120, currently entering phase III clinical development.


  • Organizational Affiliation

    Boehringer Ingelheim Austria GmbH, Vienna, Austria and Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. frank.hilberg@vie.boehringer-ingelheim.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vascular endothelial growth factor receptor 2316Homo sapiensMutation(s): 0 
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
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
XIN BindingDB:  3C7Q Ki: 3.8 (nM) from 1 assay(s)
Kd: 2.9 (nM) from 1 assay(s)
IC50: min: 3.1, max: 21 (nM) from 7 assay(s)
Binding MOAD:  3C7Q IC50: 21 (nM) from 1 assay(s)
PDBBind:  3C7Q IC50: 21 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.217 
  • R-Value Observed: 0.221 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.25α = 90
b = 94.44β = 90
c = 96.22γ = 90
Software Package:
Software NamePurpose
XSCALEdata scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MAR345data collection
XDSdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2008-12-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Advisory, Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Advisory, Refinement description
  • Version 1.3: 2023-11-01
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2023-11-15
    Changes: Data collection