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PDBsum entry 3cjg
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protein ligands links
Transferase PDB id
3cjg

 

 

 

 

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Contents
Protein chain
282 a.a. *
Ligands
SO4 ×2
KIM
Waters ×116
* Residue conservation analysis
PDB id:
3cjg
Name: Transferase
Title: Crystal structure of vegfr2 in complex with a 3,4,5-trimethoxy aniline containing pyrimidine
Structure: Vascular endothelial growth factor receptor 2. Chain: a. Fragment: kinase domain. Residues 806-939 and 994-1168. Synonym: vegfr-2, kinase insert domain receptor, protein-tyrosine kinase receptor flk-1, cd309 antigen. Engineered: yes
Source: Homo sapiens. Human. Gene: kdr, flk1. Expressed in: spodoptera frugiperda. Other_details: kid insert removed
Resolution:
2.25Å     R-factor:   0.209     R-free:   0.253
Authors: R.T.Nolte
Key ref: P.A.Harris et al. (2008). Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem, 51, 4632-4640. PubMed id: 18620382
Date:
12-Mar-08     Release date:   07-Oct-08    
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.
282 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: 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 51:4632-4640 (2008)
PubMed id: 18620382  
 
 
Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor.
P.A.Harris, A.Boloor, M.Cheung, R.Kumar, R.M.Crosby, R.G.Davis-Ward, A.H.Epperly, K.W.Hinkle, R.N.Hunter, J.H.Johnson, V.B.Knick, C.P.Laudeman, D.K.Luttrell, R.A.Mook, R.T.Nolte, S.K.Rudolph, J.R.Szewczyk, A.T.Truesdale, J.M.Veal, L.Wang, J.A.Stafford.
 
  ABSTRACT  
 
Inhibition of the vascular endothelial growth factor (VEGF) signaling pathway has emerged as one of the most promising new approaches for cancer therapy. We describe herein the key steps starting from an initial screening hit leading to the discovery of pazopanib, N(4)-(2,3-dimethyl-2H-indazol-6-yl)-N(4)-methyl-N(2)-(4-methyl-3-sulfonamidophenyl)-2,4-pyrimidinediamine, a potent pan-VEGF receptor (VEGFR) inhibitor under clinical development for renal-cell cancer and other solid tumors.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21170513 A.Truong, T.Y.Wong, and L.M.Khachigian (2011).
Emerging therapeutic approaches in the management of retinal angiogenesis and edema.
  J Mol Med, 89, 343-361.  
20456972 F.A.Schutz, T.K.Choueiri, and C.N.Sternberg (2011).
Pazopanib: Clinical development of a potent anti-angiogenic drug.
  Crit Rev Oncol Hematol, 77, 163-171.  
20881954 B.C.Goh, N.J.Reddy, U.B.Dandamudi, K.H.Laubscher, T.Peckham, J.P.Hodge, A.B.Suttle, T.Arumugham, Y.Xu, C.F.Xu, J.Lager, M.M.Dar, and L.D.Lewis (2010).
An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5+1 cocktail in patients with advanced solid tumors.
  Clin Pharmacol Ther, 88, 652-659.  
  21049083 C.L.Cowey, G.Sonpavde, and T.E.Hutson (2010).
New advancements and developments in treatment of renal cell carcinoma: focus on pazopanib.
  Onco Targets Ther, 3, 147-155.  
20000789 J.Kocí, A.G.Oliver, and V.Krchnák (2010).
Unprecedented rearrangement of 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides to 2,3-dihydro-1H-imidazo[1,2-b]indazoles.
  J Org Chem, 75, 502-505.  
20381423 K.A.Furge, J.P.MacKeigan, and B.T.Teh (2010).
Kinase targets in renal-cell carcinomas: reassessing the old and discovering the new.
  Lancet Oncol, 11, 571-578.  
20546782 L.Arko, I.Katsyv, G.E.Park, W.P.Luan, and J.K.Park (2010).
Experimental approaches for the treatment of malignant gliomas.
  Pharmacol Ther, 128, 1.  
20714356 P.E.Clark (2010).
Rationale for targeted therapies and potential role of pazopanib in advanced renal cell carcinoma.
  Biologics, 4, 187-197.  
20043026 R.M.Bukowski, U.Yasothan, and P.Kirkpatrick (2010).
Pazopanib.
  Nat Rev Drug Discov, 9, 17-18.  
20469994 R.M.Bukowski (2010).
Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma.
  Expert Rev Anticancer Ther, 10, 635-645.  
20448661 W.M.Linehan, R.Srinivasan, and L.S.Schmidt (2010).
The genetic basis of kidney cancer: a metabolic disease.
  Nat Rev Urol, 7, 277-285.  
19903063 C.A.Castaneda, and H.L.Gomez (2009).
Pazopanib: an antiangiogenic drug in perspective.
  Future Oncol, 5, 1335-1348.  
19749798 K.A.Olaussen, F.Commo, M.Tailler, L.Lacroix, I.Vitale, S.Q.Raza, C.Richon, P.Dessen, V.Lazar, J.C.Soria, and G.Kroemer (2009).
Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines.
  Oncogene, 28, 4249-4260.  
19582291 M.Radi, S.Schenone, and M.Botta (2009).
Recent highlights in the synthesis of highly functionalized pyrimidines.
  Org Biomol Chem, 7, 2841-2847.  
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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