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PDBsum entry 4gv1

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Transferase/transferase inhibitor PDB id
4gv1
Jmol PyMol
Contents
Protein chain
330 a.a.
Ligands
0XZ
GOL ×4
Waters ×393
PDB id:
4gv1
Name: Transferase/transferase inhibitor
Title: Pkb alpha in complex with azd5363
Structure: Rac-alpha serine/threonine-protein kinase. Chain: a. Fragment: kinase domain (unp residues 144-480). Synonym: protein kinase b, pkb, protein kinase b alpha, pkb proto-oncogenE C-akt, rac-pk-alpha. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: akt1, pkb, rac. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
Resolution:
1.49Å     R-factor:   0.182     R-free:   0.210
Authors: M.Addie,P.Ballard,G.Bird,D.Buttar,G.Currie,B.Davies,J.Debrec H.Dry,P.Dudley,R.Greenwood,G.Hatter,A.Jestel,P.D.Johnson,J. C.Lane,G.Lamont,A.Leach,R.W.A.Luke,D.Ogilvie,K.Page,M.Pass, S.Steinbacher,H.Steuber,S.Pearson,L.Ruston
Key ref: M.Addie et al. (2013). Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem, 56, 2059-2073. PubMed id: 23394218 DOI: 10.1021/jm301762v
Date:
30-Aug-12     Release date:   27-Feb-13    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P31749  (AKT1_HUMAN) -  RAC-alpha serine/threonine-protein kinase
Seq:
Struc:
480 a.a.
330 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 3 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: E.C.2.7.11.1  - Non-specific serine/threonine protein 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!
  Biological process     protein phosphorylation   1 term 
  Biochemical function     protein kinase activity     3 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm301762v J Med Chem 56:2059-2073 (2013)
PubMed id: 23394218  
 
 
Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases.
M.Addie, P.Ballard, D.Buttar, C.Crafter, G.Currie, B.R.Davies, J.Debreczeni, H.Dry, P.Dudley, R.Greenwood, P.D.Johnson, J.G.Kettle, C.Lane, G.Lamont, A.Leach, R.W.Luke, J.Morris, D.Ogilvie, K.Page, M.Pass, S.Pearson, L.Ruston.
 
  ABSTRACT  
 
Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.
 

 

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