5EW3

Human Vascular Endothelial Growth Factor Receptor 2 (KDR) Kinase Domain in complex with AAL993


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.219 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Novel Potent Oral Series of VEGFR2 Inhibitors Abrogate Tumor Growth by Inhibiting Angiogenesis.

Bold, G.Schnell, C.Furet, P.McSheehy, P.Bruggen, J.Mestan, J.Manley, P.W.Druckes, P.Burglin, M.Durler, U.Loretan, J.Reuter, R.Wartmann, M.Theuer, A.Bauer-Probst, B.Martiny-Baron, G.Allegrini, P.Goepfert, A.Wood, J.Littlewood-Evans, A.

(2016) J Med Chem 59: 132-146

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01582
  • Primary Citation of Related Structures:  
    5EW3

  • PubMed Abstract: 

    This paper describes the identification of 6-(pyrimidin-4-yloxy)-naphthalene-1-carboxamides as a new class of potent and selective human vascular endothelial growth factor receptor 2 (VEGFR2) tyrosine kinase inhibitors. In biochemical and cellular assays, the compounds exhibit single-digit nanomolar potency toward VEGFR2. Compounds of this series show good exposure in rodents when dosed orally. They potently inhibit VEGF-driven angiogenesis in a chamber model and rodent tumor models at daily doses of less than 3 mg/kg by targeting the tumor vasculature as demonstrated by ELISA for TIE-2 in lysates or by immunohistochemical analysis. This novel series of compounds shows a potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.


  • Organizational Affiliation

    Oncology Research, Novartis Institutes for BioMedical Research , 4002 Basel, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Vascular endothelial growth factor receptor 2
A, B
316Homo sapiensMutation(s): 0 
Gene Names: KDRFLK1VEGFR2
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5T2
Query on 5T2

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
2-(pyridin-4-ylmethylamino)-~{N}-[3-(trifluoromethyl)phenyl]benzamide
C20 H16 F3 N3 O
BLAFVGLBBOPRLP-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5T2 BindingDB:  5EW3 IC50: min: 1.2, max: 170 (nM) from 7 assay(s)
Binding MOAD:  5EW3 IC50: 1.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.219 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.5α = 90
b = 55.76β = 92.28
c = 89.76γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-12-16
    Type: Initial release
  • Version 1.1: 2016-01-27
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Refinement description