3IKA

Crystal Structure of EGFR 696-1022 T790M Mutant Covalently Binding to WZ4002


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Novel mutant-selective EGFR kinase inhibitors against EGFR T790M.

Zhou, W.Ercan, D.Chen, L.Yun, C.H.Li, D.Capelletti, M.Cortot, A.B.Chirieac, L.Iacob, R.E.Padera, R.Engen, J.R.Wong, K.K.Eck, M.J.Gray, N.S.Janne, P.A.

(2009) Nature 462: 1070-1074

  • DOI: https://doi.org/10.1038/nature08622
  • Primary Citation of Related Structures:  
    3IKA

  • PubMed Abstract: 

    The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.


  • Organizational Affiliation

    Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor
A, B
331Homo sapiensMutation(s): 1 
Gene Names: EGFRERBB1
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
0UN
Query on 0UN

Download Ideal Coordinates CCD File 
C [auth A]N-{3-[(5-chloro-2-{[2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)oxy]phenyl}prop-2-enamide
C25 H27 Cl N6 O3
ITTRLTNMFYIYPA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
0UN BindingDB:  3IKA Kd: min: 0.3, max: 46 (nM) from 4 assay(s)
IC50: min: 0.04, max: 120 (nM) from 32 assay(s)
EC50: min: 26, max: 989 (nM) from 5 assay(s)
PDBBind:  3IKA IC50: 14 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.23α = 90
b = 89.126β = 90
c = 165.224γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
REFMACrefinement
DENZOdata reduction
SCALEPACKdata 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: 2010-01-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-13
    Changes: Database references, Derived calculations