PDBsum entry 2fvd

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Transferase PDB id
Protein chain
284 a.a. *
Waters ×179
* Residue conservation analysis
PDB id:
Name: Transferase
Title: Cyclin dependent kinase 2 (cdk2) with diaminopyrimidine inhibitor
Structure: Cell division protein kinase 2. Chain: a. Synonym: p33 protein kinase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: unidentified baculovirus. Expression_system_taxid: 10469
1.85Å     R-factor:   0.207     R-free:   0.235
Authors: R.L.Crowther,C.M.Lukacs,R.U.Kammlott
Key ref: X.J.Chu et al. (2006). Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity. J Med Chem, 49, 6549-6560. PubMed id: 17064073 DOI: 10.1021/jm0606138
30-Jan-06     Release date:   10-Oct-06    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
298 a.a.
284 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/jm0606138 J Med Chem 49:6549-6560 (2006)
PubMed id: 17064073  
Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6- methoxyphenyl)methanone (R547), a potent and selective cyclin-dependent kinase inhibitor with significant in vivo antitumor activity.
X.J.Chu, W.DePinto, D.Bartkovitz, S.S.So, B.T.Vu, K.Packman, C.Lukacs, Q.Ding, N.Jiang, K.Wang, P.Goelzer, X.Yin, M.A.Smith, B.X.Higgins, Y.Chen, Q.Xiang, J.Moliterni, G.Kaplan, B.Graves, A.Lovey, N.Fotouhi.
The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i) > 10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

Literature references that cite this PDB file's key reference

  PubMed id Reference
21507639 J.B.Perales, J.Freeman, C.J.Bacchi, T.Bowling, R.Don, E.Gaukel, L.Mercer, J.A.Moore, B.Nare, T.M.Nguyen, R.A.Noe, R.Randolph, C.Rewerts, S.A.Wring, N.Yarlett, and R.T.Jacobs (2011).
SAR of 2-amino and 2,4-diamino pyrimidines with in vivo efficacy against Trypanosoma brucei.
  Bioorg Med Chem Lett, 21, 2816-2819.  
21347454 L.Mercer, T.Bowling, J.Perales, J.Freeman, T.Nguyen, C.Bacchi, N.Yarlett, R.Don, R.Jacobs, and B.Nare (2011).
2,4-Diaminopyrimidines as Potent Inhibitors of Trypanosoma brucei and Identification of Molecular Targets by a Chemical Proteomics Approach.
  PLoS Negl Trop Dis, 5, e956.  
21286784 P.Dobeš, J.Fanfrlík, J.Rezáč, M.Otyepka, and P.Hobza (2011).
Transferable scoring function based on semiempirical quantum mechanical PM6-DH2 method: CDK2 with 15 structurally diverse inhibitors.
  J Comput Aided Mol Des, 25, 223-235.  
20670437 A.Ocaña, and A.Pandiella (2010).
Personalized therapies in the cancer "omics" era.
  Mol Cancer, 9, 202.  
20577054 S.M.Johnson, C.D.Torrice, J.F.Bell, K.B.Monahan, Q.Jiang, Y.Wang, M.R.Ramsey, J.Jin, K.K.Wong, L.Su, D.Zhou, and N.E.Sharpless (2010).
Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition.
  J Clin Invest, 120, 2528-2536.  
19582291 M.Radi, S.Schenone, and M.Botta (2009).
Recent highlights in the synthesis of highly functionalized pyrimidines.
  Org Biomol Chem, 7, 2841-2847.  
18054800 M.Malumbres, P.Pevarello, M.Barbacid, and J.R.Bischoff (2008).
CDK inhibitors in cancer therapy: what is next?
  Trends Pharmacol Sci, 29, 16-21.  
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.  
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