2RGP | pdb_00002rgp

Structure of EGFR in complex with hydrazone, a potent dual inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 
    0.268 (Depositor), 0.260 (DCC) 
  • R-Value Work: 
    0.228 (Depositor), 0.220 (DCC) 

Starting Model: experimental
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Ligand Structure Quality Assessment 

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This is version 1.3 of the entry. See complete history. 


Literature

4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors.

Xu, G., Abad, M.C., Connolly, P.J., Neeper, M.P., Struble, G.T., Springer, B.A., Emanuel, S.L., Pandey, N., Gruninger, R.H., Adams, M., Moreno-Mazza, S., Fuentes-Pesquera, A.R., Middleton, S.A.

(2008) Bioorg Med Chem Lett 18: 4615-4619

  • DOI: https://doi.org/10.1016/j.bmcl.2008.07.020
  • Primary Citation of Related Structures:  
    2RGP

  • PubMed Abstract: 

    Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.

    • Organizational Affiliation: 

    Johnson & Johnson Pharmaceutical Research and Development, Medicinal Chemistry, 8 Clarke Drive, Cranbury, NJ 08512, USA. gxu4@prdus.jnj.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Epidermal growth factor receptor315Homo sapiensMutation(s): 0 
Gene Names: EGFR, ERBB1
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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free:  0.268 (Depositor), 0.260 (DCC) 
  • R-Value Work:  0.228 (Depositor), 0.220 (DCC) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.85α = 90
b = 68.03β = 90
c = 103.86γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted HYZClick on this verticalbar to view details

View more in-depth experimental data
Entry History 

Deposition Data

  • Released Date: 2008-08-26 
    • Deposition Author(s): Abad, M.C.

Revision History  (Full details and data files)

  • Version 1.0: 2008-08-26
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description