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PDBsum entry 2wxv

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2wxv
Jmol
Contents
Protein chains
302 a.a. *
257 a.a. *
Ligands
WXV ×2
SO4
Waters ×140
* Residue conservation analysis
PDB id:
2wxv
Name: Transferase
Title: Structure of cdk2-cyclin a with a pyrazolo(4,3-h) quinazoline-3-carboxamide inhibitor
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase. Engineered: yes. Cyclin-a2. Chain: b, d. Fragment: c-terminal portion, residues 173-432. Synonym: cyclin a2, cyclin-a. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: highfive. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Resolution:
2.60Å     R-factor:   0.211     R-free:   0.243
Authors: G.Traquandi,M.Ciomei,D.Ballinari,E.Casale,N.Colombo,V.Croci, F.Fiorentini,A.Isacchi,A.Longo,C.Mercurio,A.Panzeri, W.Pastori,P.Pevarello,D.Volpi,P.Roussel,A.Vulpetti, M.G.Brasca
Key ref: G.Traquandi et al. (2010). Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors. J Med Chem, 53, 2171-2187. PubMed id: 20141146 DOI: 10.1021/jm901710h
Date:
10-Nov-09     Release date:   23-Feb-10    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
302 a.a.
Protein chains
Pfam   ArchSchema ?
P20248  (CCNA2_HUMAN) -  Cyclin-A2
Seq:
Struc:
432 a.a.
257 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chains A, C: E.C.2.7.11.22  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
ATP
+ protein
= ADP
+ phosphoprotein
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   30 terms 
  Biochemical function     nucleotide binding     13 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm901710h J Med Chem 53:2171-2187 (2010)
PubMed id: 20141146  
 
 
Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors.
G.Traquandi, M.Ciomei, D.Ballinari, E.Casale, N.Colombo, V.Croci, F.Fiorentini, A.Isacchi, A.Longo, C.Mercurio, A.Panzeri, W.Pastori, P.Pevarello, D.Volpi, P.Roussel, A.Vulpetti, M.G.Brasca.
 
  ABSTRACT  
 
Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.