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PDBsum entry 2bpm

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2bpm
Jmol
Contents
Protein chains
302 a.a. *
258 a.a. *
Ligands
529 ×2
SO4 ×2
Waters ×414
* Residue conservation analysis
PDB id:
2bpm
Name: Transferase
Title: Structure of cdk2-cyclin a with pha-630529
Structure: Cell division protein kinase 2. Chain: a, c. Synonym: p33 protein kinase. Engineered: yes. Cyclin a2. Chain: b, d. Fragment: residues 174-432 (c-terminal portion). Synonym: 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.
Biol. unit: Dimer (from PDB file)
Resolution:
2.4Å     R-factor:   0.229     R-free:   0.271
Authors: A.Cameron,G.Fogliatto,P.Pevarello,M.G.Brasca,P.Orsini, G.Traquandi,A.Longo,M.Nesi,F.Orzi,C.Piutti,P.Sansonna, M.Varasi,A.Vulpetti,F.Roletto,R.Alzani,M.Ciomei,C.Albanese, W.Pastori,A.Marsiglio,E.Pesenti,F.Fiorentini,J.R.Bischoff, C.Mercurio
Key ref: P.Pevarello et al. (2005). 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization. J Med Chem, 48, 2944-2956. PubMed id: 15828833 DOI: 10.1021/jm0408870
Date:
21-Apr-05     Release date:   08-Dec-05    
PROCHECK
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 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.
258 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/jm0408870 J Med Chem 48:2944-2956 (2005)
PubMed id: 15828833  
 
 
3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization.
P.Pevarello, M.G.Brasca, P.Orsini, G.Traquandi, A.Longo, M.Nesi, F.Orzi, C.Piutti, P.Sansonna, M.Varasi, A.Cameron, A.Vulpetti, F.Roletto, R.Alzani, M.Ciomei, C.Albanese, W.Pastori, A.Marsiglio, E.Pesenti, F.Fiorentini, J.R.Bischoff, C.Mercurio.
 
  ABSTRACT  
 
Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20010939 N.Johnson, J.Bentley, L.Z.Wang, D.R.Newell, C.N.Robson, G.I.Shapiro, and N.J.Curtin (2010).
Pre-clinical evaluation of cyclin-dependent kinase 2 and 1 inhibition in anti-estrogen-sensitive and resistant breast cancer cells.
  Br J Cancer, 102, 342-350.  
17571187 F.Marchetti, K.L.Sayle, J.Bentley, W.Clegg, N.J.Curtin, J.A.Endicott, B.T.Golding, R.J.Griffin, K.Haggerty, R.W.Harrington, V.Mesguiche, D.R.Newell, M.E.Noble, R.J.Parsons, D.J.Pratt, L.Z.Wang, and I.R.Hardcastle (2007).
Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2.
  Org Biomol Chem, 5, 1577-1585.  
17450625 M.G.Brasca, C.Albanese, R.Amici, D.Ballinari, L.Corti, V.Croci, D.Fancelli, F.Fiorentini, M.Nesi, P.Orsini, F.Orzi, W.Pastori, E.Perrone, E.Pesenti, P.Pevarello, F.Riccardi-Sirtori, F.Roletto, P.Roussel, M.Varasi, A.Vulpetti, and C.Mercurio (2007).
6-Substituted Pyrrolo[3,4-c]pyrazoles: An Improved Class of CDK2 Inhibitors.
  ChemMedChem, 2, 841-852.  
16846802 G.M.Keseru, and G.M.Makara (2006).
Hit discovery and hit-to-lead approaches.
  Drug Discov Today, 11, 741-748.  
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