3QKL

Spirochromane Akt Inhibitors

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history. 


Literature

Discovery and SAR of spirochromane Akt inhibitors.

Kallan, N.C., Spencer, K.L., Blake, J.F., Xu, R., Heizer, J., Bencsik, J.R., Mitchell, I.S., Gloor, S.L., Martinson, M., Risom, T., Gross, S.D., Morales, T.H., Wu, W.I., Vigers, G.P., Brandhuber, B.J., Skelton, N.J.

(2011) Bioorg Med Chem Lett 21: 2410-2414

  • DOI: https://doi.org/10.1016/j.bmcl.2011.02.073
  • Primary Citation of Related Structures:  
    3QKK, 3QKL

  • PubMed Abstract: 

    A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA.

    • Organizational Affiliation: 

    Array BioPharma, Inc., 3200 Walnut Street, Boulder, CO 80301, USA. nkallan@arraybiopharma.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RAC-alpha serine/threonine-protein kinase341Homo sapiensMutation(s): 1 
Gene Names: AKT1, PKB, RAC
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 peptideB [auth C]10N/AMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SMR
Query on SMR
Download Ideal Coordinates CCD File 
C [auth A]N-{(2S)-3-[(3S)-8',9'-dihydro-1H,3'H-spiro[piperidine-3,7'-pyrano[3,2-e]indazol]-1-yl]-2-hydroxypropyl}-N-(2-ethoxyethyl)-2,6-dimethylbenzenesulfonamide
C29 H40 N4 O5 S
ZSKFBGIRLVOQAD-MUAVYFROSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
TPO
Query on TPO
A
L-PEPTIDE LINKINGC4 H10 N O6 PTHR
Binding Affinity Annotations 
IDSourceBinding Affinity
SMR PDBBind:  3QKL IC50: 9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.741α = 90
b = 55.72β = 101.84
c = 91.019γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-30
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance