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PDBsum entry 2uzw

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protein ligands Protein-protein interface(s) links
Transferase PDB id
2uzw
Jmol
Contents
Protein chains
336 a.a. *
20 a.a. *
Ligands
SS4
* Residue conservation analysis
PDB id:
2uzw
Name: Transferase
Title: Pka structures of indazole-pyridine series of akt inhibitors
Structure: Camp-dependent protein kinase, alpha-catalytic subunit. Chain: e. Fragment: residues 15-350. Synonym: protein kinase a, pka c-alpha. Engineered: yes. Camp-dependent protein kinase inhibitor alpha. Chain: i. Fragment: residues 5-24.
Source: Bos taurus. Bovine. Organism_taxid: 9913. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9913
Resolution:
2.20Å     R-factor:   0.313     R-free:   0.327
Authors: G.D.Zhu,V.B.Gandhi,J.Gong,S.Thomas,K.W.Woods,X.Song,T.Li, R.B.Diebold,Y.Luo,X.Liu,R.Guan,V.Klinghofer,E.F.Johnson, J.Bouska,A.Olson,K.C.Marsh,V.S.Stoll,M.Mamo,J.Polakowski, T.J.Campbell,T.D.Penning,Q.Li,S.H.Rosenberg,V.L.Giranda
Key ref: G.D.Zhu et al. (2007). Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension. J Med Chem, 50, 2990-3003. PubMed id: 17523610 DOI: 10.1021/jm0701019
Date:
01-May-07     Release date:   05-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P00517  (KAPCA_BOVIN) -  cAMP-dependent protein kinase catalytic subunit alpha
Seq:
Struc:
351 a.a.
336 a.a.*
Protein chain
Pfam   ArchSchema ?
Q3SX13  (IPKA_BOVIN) -  cAMP-dependent protein kinase inhibitor alpha
Seq:
Struc:
76 a.a.
20 a.a.
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: Chain E: E.C.2.7.11.11  - cAMP-dependent 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!
  Cellular component     sperm midpiece   11 terms 
  Biological process     regulation of proteasomal protein catabolic process   19 terms 
  Biochemical function     nucleotide binding     14 terms  

 

 
    reference    
 
 
DOI no: 10.1021/jm0701019 J Med Chem 50:2990-3003 (2007)
PubMed id: 17523610  
 
 
Syntheses of potent, selective, and orally bioavailable indazole-pyridine series of protein kinase B/Akt inhibitors with reduced hypotension.
G.D.Zhu, V.B.Gandhi, J.Gong, S.Thomas, K.W.Woods, X.Song, T.Li, R.B.Diebold, Y.Luo, X.Liu, R.Guan, V.Klinghofer, E.F.Johnson, J.Bouska, A.Olson, K.C.Marsh, V.S.Stoll, M.Mamo, J.Polakowski, T.J.Campbell, R.L.Martin, G.A.Gintant, T.D.Penning, Q.Li, S.H.Rosenberg, V.L.Giranda.
 
  ABSTRACT  
 
Compound 7 was identified as a potent (IC50 = 14 nM), selective, and orally bioavailable (F = 70% in mouse) inhibitor of protein kinase B/Akt. While promising efficacy was observed in vivo, this compound showed effects on depolarization of Purkinje fibers in an in vitro assay and CV hypotension in vivo. Guided by an X-ray structure of 7 bound to protein kinase A, which has 80% homology with Akt in the kinase domain, our efforts have focused on structure-activity relationship (SAR) studies of the phenyl moiety, in an attempt to address the cardiovascular liability and further improve the Akt potency. A novel and efficient synthetic route toward diversely substituted phenyl derivatives of 7 was developed utilizing a copper-mediated aziridine ring-opening reaction as the key step. To improve the selectivity of these Akt inhibitors over other protein kinases, a nitrogen atom was incorporated into selected phenyl analogues of 7 at the C-6 position of the methyl indazole scaffold. These modifications resulted in the discovery of inhibitor 37c with greater potency (IC50 = 0.6 nM vs Akt), selectivity, and improved cardiovascular safety profile. The SARs, pharmacokinetic profile, and CV safety of selected Akt inhibitors will be discussed.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20000789 J.Kocí, A.G.Oliver, and V.Krchnák (2010).
Unprecedented rearrangement of 2-(2-aminoethyl)-1-aryl-3,4-dihydropyrazino[1,2-b]indazole-2-ium 6-oxides to 2,3-dihydro-1H-imidazo[1,2-b]indazoles.
  J Org Chem, 75, 502-505.  
21042610 S.M.Wales, A.C.Willis, and P.A.Keller (2010).
The first syntheses of enantiopure 2,2'-biindoline.
  Chem Commun (Camb), 46, 9226-9228.  
20689981 S.Qian, J.Cao, Y.Yan, M.Sun, H.Zhu, Y.Hu, Q.He, and B.Yang (2010).
SMT-A07, a 3-(Indol-2-yl) indazole derivative, induces apoptosis of leukemia cells in vitro.
  Mol Cell Biochem, 345, 13-21.  
  20616901 E.Calvo, V.Bolós, and E.Grande (2009).
Multiple roles and therapeutic implications of Akt signaling in cancer.
  Onco Targets Ther, 2, 135-150.  
19043747 M.Muddassar, F.A.Pasha, M.M.Neaz, Y.Saleem, and S.J.Cho (2009).
Elucidation of binding mode and three dimensional quantitative structure-activity relationship studies of a novel series of protein kinase B/Akt inhibitors.
  J Mol Model, 15, 183-192.  
19053772 D.Mukkamala, J.H.No, L.M.Cass, T.K.Chang, and E.Oldfield (2008).
Bisphosphonate inhibition of a Plasmodium farnesyl diphosphate synthase and a general method for predicting cell-based activity from enzyme data.
  J Med Chem, 51, 7827-7833.  
18937414 I.Bouillon, J.Zajícek, N.Pudelová, and V.Krchnák (2008).
Remarkably efficient synthesis of 2H-indazole 1-oxides and 2H-indazoles via tandem carbon-carbon followed by nitrogen-nitrogen bond formation.
  J Org Chem, 73, 9027-9032.  
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.