4LI5

EGFR-K IN COMPLEX WITH N-[3-[[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]-4-methoxy-phenyl] Prop-2-enamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.64 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure- and Reactivity-Based Development of Covalent Inhibitors of the Activating and Gatekeeper Mutant Forms of the Epidermal Growth Factor Receptor (EGFR).

Ward, R.A.Anderton, M.J.Ashton, S.Bethel, P.A.Box, M.Butterworth, S.Colclough, N.Chorley, C.G.Chuaqui, C.Cross, D.A.Dakin, L.A.Debreczeni, J.E.Eberlein, C.Finlay, M.R.Hill, G.B.Grist, M.Klinowska, T.C.Lane, C.Martin, S.Orme, J.P.Smith, P.Wang, F.Waring, M.J.

(2013) J Med Chem 56: 7025-7048

  • DOI: https://doi.org/10.1021/jm400822z
  • Primary Citation of Related Structures:  
    4LI5

  • PubMed Abstract: 

    A novel series of small-molecule inhibitors has been developed to target the double mutant form of the epidermal growth factor receptor (EGFR) tyrosine kinase, which is resistant to treatment with gefitinib and erlotinib. Our reported compounds also show selectivity over wild-type EGFR. Guided by molecular modeling, this series was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and demonstrates high levels of activity in cellular models of the double mutant form of EGFR. In addition, these compounds show significant activity against the activating mutations, which gefitinib and erlotinib target and inhibition of which gives rise to their observed clinical efficacy. A glutathione (GSH)-based assay was used to measure thiol reactivity toward the electrophilic functionality of the inhibitor series, enabling both the identification of a suitable reactivity window for their potency and the development of a reactivity quantitative structure-property relationship (QSPR) to support design.


  • Organizational Affiliation

    AstraZeneca , Oncology & Discovery Sciences Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor328Homo sapiensMutation(s): 0 
Gene Names: EGFRERBBERBB1HER1
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P00533 (Homo sapiens)
Explore P00533 
Go to UniProtKB:  P00533
PHAROS:  P00533
GTEx:  ENSG00000146648 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00533
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1WY
Query on 1WY

Download Ideal Coordinates CCD File 
B [auth A]N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxyphenyl)propanamide
C22 H20 Cl N5 O2
WBICYBFULYQLHC-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1WY PDBBind:  4LI5 IC50: 550 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.64 Å
  • R-Value Free: 0.203 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: I 2 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 144.892α = 90
b = 144.892β = 90
c = 144.892γ = 90
Software Package:
Software NamePurpose
DA+data collection
PHASERphasing
REFMACrefinement
XDSdata reduction
XSCALEdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-08-28
    Type: Initial release
  • Version 1.1: 2013-09-25
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations