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PDBsum entry 4bgh

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protein ligands links
Transferase PDB id
4bgh
Jmol
Contents
Protein chain
275 a.a.
Ligands
3I6
Waters ×52
PDB id:
4bgh
Name: Transferase
Title: Crystal structure of cdk2 in complex with pan-cdk inhibitor
Structure: Cyclin-dependent kinase 2. Chain: a. Fragment: catalytic domain, residues 1-298. Synonym: cell division protein kinase 2, p33 protein kinase engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Resolution:
1.95Å     R-factor:   0.195     R-free:   0.246
Authors: U.Luecking,R.Jautelat,M.Krueger,T.Brumby,P.Lienau,M.Schaefer J.Schulze,A.Hillisch,A.Reichel,G.Siemeister
Key ref: U.Lücking et al. (2013). The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer. ChemMedChem, 8, 1067-1085. PubMed id: 23671017 DOI: 10.1002/cmdc.201300096
Date:
26-Mar-13     Release date:   04-Sep-13    
PROCHECK
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 Headers
 References

Protein chain
Pfam   ArchSchema ?
P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2
Seq:
Struc:
298 a.a.
275 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     cyclin-dependent protein kinase holoenzyme complex   15 terms 
  Biological process     regulation of gene silencing   27 terms 
  Biochemical function     nucleotide binding     12 terms  

 

 
    reference    
 
 
DOI no: 10.1002/cmdc.201300096 ChemMedChem 8:1067-1085 (2013)
PubMed id: 23671017  
 
 
The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4-{[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer.
U.Lücking, R.Jautelat, M.Krüger, T.Brumby, P.Lienau, M.Schäfer, H.Briem, J.Schulze, A.Hillisch, A.Reichel, A.M.Wengner, G.Siemeister.
 
  ABSTRACT  
 
Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan-CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials.