spacer
spacer

PDBsum entry 2wih

Go to PDB code: 
protein ligands Protein-protein interface(s) links
Transferase PDB id
2wih
Jmol
Contents
Protein chains
302 a.a. *
257 a.a. *
Ligands
P48 ×2
SO4
Waters ×214
* Residue conservation analysis
PDB id:
2wih
Name: Transferase
Title: Structure of cdk2-cyclin a with pha-848125
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 a, cyclin a2. 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:
2.50Å     R-factor:   0.215     R-free:   0.250
Authors: M.G.Brasca,N.Amboldi,D.Ballinari,A.D.Cameron,E.Casale, G.Cervi,M.Colombo,F.Colotta,V.Croci,R.Dalessio, F.Fiorentini,A.Isacchi,C.Mercurio,W.Moretti,A.Panzeri, W.Pastori,P.Pevarello,F.Quartieri,F.Roletto,G.Traquandi, P.Vianello,A.Vulpetti,M.Ciomei
Key ref: M.G.Brasca et al. (2009). Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem, 52, 5152-5163. PubMed id: 19603809
Date:
13-May-09     Release date:   28-Jul-09    
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    
 
 
J Med Chem 52:5152-5163 (2009)
PubMed id: 19603809  
 
 
Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.
M.G.Brasca, N.Amboldi, D.Ballinari, A.Cameron, E.Casale, G.Cervi, M.Colombo, F.Colotta, V.Croci, R.D'Alessio, F.Fiorentini, A.Isacchi, C.Mercurio, W.Moretti, A.Panzeri, W.Pastori, P.Pevarello, F.Quartieri, F.Roletto, G.Traquandi, P.Vianello, A.Vulpetti, M.Ciomei.
 
  ABSTRACT  
 
The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21440449 V.M.Yenugonda, T.B.Deb, S.C.Grindrod, S.Dakshanamurthy, Y.Yang, M.Paige, and M.L.Brown (2011).
Fluorescent cyclin-dependent kinase inhibitors block the proliferation of human breast cancer cells.
  Bioorg Med Chem, 19, 2714-2725.  
20679242 F.Iorio, R.Bosotti, E.Scacheri, V.Belcastro, P.Mithbaokar, R.Ferriero, L.Murino, R.Tagliaferri, N.Brunetti-Pierri, A.Isacchi, and D.di Bernardo (2010).
Discovery of drug mode of action and drug repositioning from transcriptional responses.
  Proc Natl Acad Sci U S A, 107, 14621-14626.  
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.