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PDBsum entry 2qu6
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protein ligands Protein-protein interface(s) links
Transferase PDB id
2qu6

 

 

 

 

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Contents
Protein chains
283 a.a. *
260 a.a. *
Ligands
SO4
857 ×2
Waters ×232
* Residue conservation analysis
PDB id:
2qu6
Name: Transferase
Title: Crystal structure of the vegfr2 kinase domain in complex with a benzoxazole inhibitor
Structure: Vascular endothelial growth factor receptor 2. Chain: a, b. Fragment: kinase domain. Synonym: vegfr-2, kinase insert domain receptor, protein-tyrosine kinase receptor flk-1, cd309 antigen. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: kdr, flk1. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.
Resolution:
2.10Å     R-factor:   0.242     R-free:   0.272
Authors: D.A.Whittington,J.L.Kim,A.M.Long,P.Rose,Y.Gu,H.Zhao
Key ref: M.H.Potashman et al. (2007). Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors. J Med Chem, 50, 4351-4373. PubMed id: 17696416
Date:
03-Aug-07     Release date:   25-Sep-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1356 a.a.
283 a.a.*
Protein chain
Pfam   ArchSchema ?
P35968  (VGFR2_HUMAN) -  Vascular endothelial growth factor receptor 2 from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		 
Seq:
Struc: 		1356 a.a.
260 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 11 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains A, B: E.C.2.7.10.1  - receptor protein-tyrosine kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H+
L-tyrosyl-[protein]
 + ATP
 = O-phospho-L-tyrosyl-[protein]
 + ADP
 + H(+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 

 
    Added reference    
 
 
J Med Chem 50:4351-4373 (2007)
PubMed id: 17696416  
 
 
Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors.
M.H.Potashman, J.Bready, A.Coxon, T.M.DeMelfi, L.DiPietro, N.Doerr, D.Elbaum, J.Estrada, P.Gallant, J.Germain, Y.Gu, J.C.Harmange, S.A.Kaufman, R.Kendall, J.L.Kim, G.N.Kumar, A.M.Long, S.Neervannan, V.F.Patel, A.Polverino, P.Rose, S.v.Plas, D.Whittington, R.Zanon, H.Zhao.
 
  ABSTRACT  
 
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21447431 G.Marzaro, A.Chilin, A.Guiotto, E.Uriarte, P.Brun, I.Castagliuolo, F.Tonus, and H.González-Díaz (2011).
Using the TOPS-MODE approach to fit multi-target QSAR models for tyrosine kinases inhibitors.
  Eur J Med Chem, 46, 2185-2192.  
21186392 J.Peng, C.Zong, M.Ye, T.Chen, D.Gao, Y.Wang, and C.Chen (2011).
Direct transition-metal-free intramolecular C-O bond formation: synthesis of benzoxazole derivatives.
  Org Biomol Chem, 9, 1225-1230.  
21210064 R.C.Jones, M.W.Chojnacka, J.W.Quail, M.G.Gardiner, A.Decken, B.F.Yates, and R.A.Gossage (2011).
Oxazoles revisited: On the nature of binding of benzoxazole and 2-methylbenzoxazole with the zinc and palladium halides.
  Dalton Trans, 40, 1594-1600.  
21543226 S.Ramurthy, M.Aikawa, P.Amiri, A.Costales, A.Hashash, J.M.Jansen, S.Lin, S.Ma, P.A.Renhowe, C.M.Shafer, S.Subramanian, L.Sung, and J.Verhagen (2011).
Design and synthesis of 5,6-fused heterocyclic amides as Raf kinase inhibitors.
  Bioorg Med Chem Lett, 21, 3286-3289.  
19921722 A.Papakyriakou, M.E.Katsarou, M.Belimezi, M.Karpusas, and D.Vourloumis (2010).
Discovery of potent vascular endothelial growth factor receptor-2 inhibitors.
  ChemMedChem, 5, 118-129.  
20963217 P.Saha, M.A.Ali, P.Ghosh, and T.Punniyamurthy (2010).
Cobalt-catalyzed intramolecular C-N and C-O cross-coupling reactions: synthesis of benzimidazoles and benzoxazoles.
  Org Biomol Chem, 8, 5692-5699.  
19795888 K.D.Park, P.Morieux, C.Salomé, S.W.Cotten, O.Reamtong, C.Eyers, S.J.Gaskell, J.P.Stables, R.Liu, and H.Kohn (2009).
Lacosamide isothiocyanate-based agents: novel agents to target and identify lacosamide receptors.
  J Med Chem, 52, 6897-6911.  
19296866 L.N.Johnson (2009).
Protein kinase inhibitors: contributions from structure to clinical compounds.
  Q Rev Biophys, 42, 1.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.

 

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