2ZM3

Complex Structure of Insulin-like Growth Factor Receptor and Isoquinolinedione Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.204 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Lead identification to generate isoquinolinedione inhibitors of insulin-like growth factor receptor (IGF-1R) for potential use in cancer treatment

Mayer, S.C.Banker, A.L.Boschelli, F.Di, L.Johnson, M.Kenny, C.H.Krishnamurthy, G.Kutterer, K.Moy, F.Petusky, S.Ravi, M.Tkach, D.Tsou, H.R.Xu, W.

(2008) Bioorg Med Chem Lett 18: 3641-3645

  • DOI: https://doi.org/10.1016/j.bmcl.2008.04.044
  • Primary Citation of Related Structures:  
    2ZM3

  • PubMed Abstract: 

    Insulin-like growth factor receptor (IGF-1R) is a growth factor receptor tyrosine kinase that acts as a critical mediator of cell proliferation and survival. This receptor is over-expressed or activated in tumor cells and is emerging as a novel target in cancer therapy. Efforts in our "Hit to Lead" group have generated a novel series of submicromolar IGF-1R inhibitors based on a isoquinolinedione template originating from a Lance enzyme HTS screen. Chemical triage and parallel synthesis incorporating focused library arrays were instrumental in moving these investigations through the Wyeth exploratory medicinal chemistry process. The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described.


  • Organizational Affiliation

    Wyeth Research, Chemical & Screening Sciences, 865 Ridge Road, Monmouth Junction, Princeton, NJ 08852, USA. mayers@wyeth.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin-like growth factor 1 receptor
A, B, C, D
308Homo sapiensMutation(s): 0 
Gene Names: IGF1R
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P08069 (Homo sapiens)
Explore P08069 
Go to UniProtKB:  P08069
PHAROS:  P08069
GTEx:  ENSG00000140443 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08069
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B, C, D
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
575 PDBBind:  2ZM3 Kd: 614 (nM) from 1 assay(s)
Binding MOAD:  2ZM3 Kd: 614 (nM) from 1 assay(s)
BindingDB:  2ZM3 IC50: 2420 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.201 
  • R-Value Observed: 0.204 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 137.725α = 90
b = 135.962β = 114.27
c = 86.38γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
ADSCdata collection
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-06-10
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-11-15
    Changes: Data collection