3OW4

Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 

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Ligand Structure Quality Assessment 


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Literature

Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.

Bencsik, J.R.Xiao, D.Blake, J.F.Kallan, N.C.Mitchell, I.S.Spencer, K.L.Xu, R.Gloor, S.L.Martinson, M.Risom, T.Woessner, R.D.Dizon, F.Wu, W.I.Vigers, G.P.Brandhuber, B.J.Skelton, N.J.Prior, W.W.Murray, L.J.

(2010) Bioorg Med Chem Lett 20: 7037-7041

  • DOI: https://doi.org/10.1016/j.bmcl.2010.09.112
  • Primary Citation of Related Structures:  
    3OW3, 3OW4

  • PubMed Abstract: 

    Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.


  • Organizational Affiliation

    Array BioPharma Inc., Boulder, CO 80301, USA. jbencsik@arraybiopharma.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RAC-alpha serine/threonine-protein kinase
A, B
341Homo sapiensMutation(s): 1 
Gene Names: AKT1PKBRAC
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P31749 (Homo sapiens)
Explore P31749 
Go to UniProtKB:  P31749
PHAROS:  P31749
GTEx:  ENSG00000142208 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP31749
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
GSK 3 beta peptide
C, D
10Homo sapiensMutation(s): 0 
Gene Names: GSK3B
UniProt & NIH Common Fund Data Resources
Find proteins for P49841 (Homo sapiens)
Explore P49841 
Go to UniProtKB:  P49841
PHAROS:  P49841
GTEx:  ENSG00000082701 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49841
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SMY
Query on SMY

Download Ideal Coordinates CCD File 
E [auth A],
F [auth B]
(2R)-3-(1H-indol-3-yl)-1-{4-[(5S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-1-oxopropan-2-amine
C22 H26 N6 O S
JGLUXTFIRPYAQV-WMLDXEAASA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A, B
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
SMY BindingDB:  3OW4 IC50: min: 22, max: 3629 (nM) from 2 assay(s)
PDBBind:  3OW4 IC50: 22 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.197 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.427α = 90
b = 55.823β = 103.93
c = 91.354γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-11-10
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance