PDBsum entry 1vyz

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protein ligands links
Transferase PDB id
Protein chain
279 a.a. *
Waters ×63
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Structure of cdk2 complexed with pnu-181227
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: highfive.
2.21Å     R-factor:   0.238     R-free:   0.280
Authors: P.Pevarello,M.G.Brasca,R.Amici,P.Orsini,G.Traquandi,L.Corti, C.Piutti,P.Sansonna,M.Villa,B.S.Pierce,M.Pulici,G.Giordano, K.Martina,E.Lfritzen,R.A.Nugent,E.Casale,A.Cameron, M.Ciomei,F.Roletto,A.Isacchi,G.Fogliatto,E.Pesenti, W.Pastori,W.Marsiglio,K.L.Leach,P.M.Clare,F.Fiorentini, M.Varasi,A.Vulpetti,M.A.Warpehoski
Key ref: P.Pevarello et al. (2004). 3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding. J Med Chem, 47, 3367-3380. PubMed id: 15189033 DOI: 10.1021/jm031145u
07-May-04     Release date:   17-Jun-04    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
298 a.a.
279 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Cyclin-dependent kinase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: ATP + a protein = ADP + a phosphoprotein
+ protein
+ 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   27 terms 
  Biochemical function     nucleotide binding     12 terms  


DOI no: 10.1021/jm031145u J Med Chem 47:3367-3380 (2004)
PubMed id: 15189033  
3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.
P.Pevarello, M.G.Brasca, R.Amici, P.Orsini, G.Traquandi, L.Corti, C.Piutti, P.Sansonna, M.Villa, B.S.Pierce, M.Pulici, P.Giordano, K.Martina, E.L.Fritzen, R.A.Nugent, E.Casale, A.Cameron, M.Ciomei, F.Roletto, A.Isacchi, G.Fogliatto, E.Pesenti, W.Pastori, A.Marsiglio, K.L.Leach, P.M.Clare, F.Fiorentini, M.Varasi, A.Vulpetti, M.A.Warpehoski.
Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.

Literature references that cite this PDB file's key reference

  PubMed id Reference
19194508 J.Xiang, H.Yang, C.Che, H.Zou, H.Yang, Y.Wei, J.Quan, H.Zhang, Z.Yang, and S.Lin (2009).
Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays.
  PLoS ONE, 4, e4361.  
19842131 M.Anzaldi, C.Macciò, M.Mazzei, M.Bertolotto, L.Ottonello, F.Dallegri, and A.Balbi (2009).
Antiproliferative and proapoptotic activities of a new class of pyrazole derivatives in HL-60 cells.
  Chem Biodivers, 6, 1674-1687.  
19015641 Z.Tang, S.Jiang, R.Du, E.T.Petri, A.El-Telbany, P.S.Chan, T.Kijima, S.Dietrich, K.Matsui, M.Kobayashi, S.Sasada, N.Okamoto, H.Suzuki, K.Kawahara, T.Iwasaki, K.Nakagawa, I.Kawase, J.G.Christensen, T.Hirashima, B.Halmos, R.Salgia, T.J.Boggon, J.A.Kern, and P.C.Ma (2009).
Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity.
  Oncogene, 28, 518-533.  
18469809 A.Montagnoli, B.Valsasina, V.Croci, M.Menichincheri, S.Rainoldi, V.Marchesi, M.Tibolla, P.Tenca, D.Brotherton, C.Albanese, V.Patton, R.Alzani, A.Ciavolella, F.Sola, A.Molinari, D.Volpi, N.Avanzi, F.Fiorentini, M.Cattoni, S.Healy, D.Ballinari, E.Pesenti, A.Isacchi, J.Moll, A.Bensimon, E.Vanotti, and C.Santocanale (2008).
A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
  Nat Chem Biol, 4, 357-365.  
18404149 D.M.Goldstein, N.S.Gray, and P.P.Zarrinkar (2008).
High-throughput kinase profiling as a platform for drug discovery.
  Nat Rev Drug Discov, 7, 391-397.  
18019530 G.Piersanti, L.Giorgi, F.Bartoccini, G.Tarzia, P.Minetti, G.Gallo, F.Giorgi, M.Castorina, O.Ghirardi, and P.Carminati (2007).
Synthesis of benzo[1,2-d;3,4-d']diimidazole and 1H-pyrazolo[4,3-b]pyridine as putative A2A receptor antagonists.
  Org Biomol Chem, 5, 2567-2571.  
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.  
16799642 A.Oloumi, S.Syam, and S.Dedhar (2006).
Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells.
  Oncogene, 25, 7747-7757.  
16253507 H.González-Díaz, D.Viña, L.Santana, Clercq, and E.Uriarte (2006).
Stochastic entropy QSAR for the in silico discovery of anticancer compounds: prediction, synthesis, and in vitro assay of new purine carbanucleosides.
  Bioorg Med Chem, 14, 1095-1107.  
16584130 J.Sridhar, N.Akula, and N.Pattabiraman (2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
  AAPS J, 8, E204-E221.  
15930768 S.Bajaj, S.S.Sambi, and A.K.Madan (2005).
Topochemical models for prediction of anti-tumor activity of 3-aminopyrazoles.
  Chem Pharm Bull (Tokyo), 53, 611-615.  
15966827 B.Valsasina, H.M.Kalisz, and A.Isacchi (2004).
Kinase selectivity profiling by inhibitor affinity chromatography.
  Expert Rev Proteomics, 1, 303-315.  
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.