2RGP

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 
  • R-Value Work: 0.228 

wwPDB Validation   3D Report Full Report


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: 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HYZ
Query on HYZ

Download Ideal Coordinates CCD File 
D [auth A]N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-5-[(piperidin-1-ylamino)methyl]pyrimidine-4,6-diamine
C24 H27 F N8
IMHOFYWDXRUQBM-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
HYZ PDBBind:  2RGP IC50: 30 (nM) from 1 assay(s)
Binding MOAD:  2RGP IC50: 30 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.228 
  • 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

View Full Validation Report



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