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PDBsum entry 4ez5

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protein ligands links
Transferase/transferase inhibitor PDB id
4ez5
Jmol
Contents
Protein chain
258 a.a.
Ligands
0RS
PDB id:
4ez5
Name: Transferase/transferase inhibitor
Title: Cdk6 (monomeric) in complex with inhibitor
Structure: Cyclin-dependent kinase 6. Chain: a. Fragment: unp residues 1-301. Synonym: cell division protein kinase 6, serine/threonine-p kinase plstire. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk6, cdkn6. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
2.70Å     R-factor:   0.220     R-free:   0.287
Authors: R.Chopra,M.Xu
Key ref: Y.S.Cho et al. (2012). Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors. ACS Med Chem Lett, 3, 445-449. PubMed id: 24900493 DOI: 10.1021/ml200241a
Date:
02-May-12     Release date:   06-Feb-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q00534  (CDK6_HUMAN) -  Cyclin-dependent kinase 6
Seq:
Struc:
326 a.a.
258 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: 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     cell projection   8 terms 
  Biological process     type B pancreatic cell development   35 terms 
  Biochemical function     nucleotide binding     10 terms  

 

 
    reference    
 
 
DOI no: 10.1021/ml200241a ACS Med Chem Lett 3:445-449 (2012)
PubMed id: 24900493  
 
 
Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
Y.S.Cho, H.Angove, C.Brain, C.H.Chen, H.Cheng, R.Cheng, R.Chopra, K.Chung, M.Congreve, C.Dagostin, D.J.Davis, R.Feltell, J.Giraldes, S.D.Hiscock, S.Kim, S.Kovats, B.Lagu, K.Lewry, A.Loo, Y.Lu, M.Luzzio, W.Maniara, R.McMenamin, P.N.Mortenson, R.Benning, M.O'Reilly, D.C.Rees, J.Shen, T.Smith, Y.Wang, G.Williams, A.J.Woolford, W.Wrona, M.Xu, F.Yang, S.Howard.
 
  ABSTRACT  
 
Herein, we describe the discovery of potent and highly selective inhibitors of both CDK4 and CDK6 via structure-guided optimization of a fragment-based screening hit. CDK6 X-ray crystallography and pharmacokinetic data steered efforts in identifying compound 6, which showed >1000-fold selectivity for CDK4 over CDKs 1 and 2 in an enzymatic assay. Furthermore, 6 demonstrated in vivo inhibition of pRb-phosphorylation and oral efficacy in a Jeko-1 mouse xenograft model.