4AGW | pdb_00004agw

Discovery of a small molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 
    0.271 (Depositor), 0.270 (DCC) 
  • R-Value Work: 
    0.226 (Depositor), 0.230 (DCC) 
  • R-Value Observed: 
    0.230 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted NG7Click on this verticalbar to view details

This is version 1.3 of the entry. See complete history


Literature

Discovery of a Small-Molecule Type II Inhibitor of Wild-Type and Gatekeeper Mutants of Bcr-Abl, Pdgfralpha, Kit, and Src Kinases: Novel Type II Inhibitor of Gatekeeper Mutants.

Weisberg, E.Choi, H.G.Ray, A.Barrett, R.Zhang, J.Sim, T.Zhou, W.Seeliger, M.Cameron, M.Azam, M.Fletcher, J.A.Debiec-Rychter, M.Mayeda, M.Moreno, D.Kung, A.L.Janne, P.A.Khosravi-Far, R.Melo, J.V.Manley, P.W.Adamia, S.Wu, C.Gray, N.Griffin, J.D.

(2010) Blood 115: 4206

  • DOI: https://doi.org/10.1182/blood-2009-11-251751
  • Primary Citation of Related Structures:  
    4AGW

  • PubMed Abstract: 

    Many clinically validated kinases, such as BCR-ABL, c-Kit, PDGFR, and EGFR, become resistant to adenosine triphosphate-competitive inhibitors through mutation of the so-called gatekeeper amino acid from a threonine to a large hydrophobic amino acid, such as an isoleucine or methionine. We have developed a new class of adenosine triphosphate competitive inhibitors, exemplified by HG-7-85-01, which is capable of inhibiting T315I- BCR-ABL (clinically observed in chronic myeloid leukemia), T670I-c-Kit (clinically observed in gastrointestinal stromal tumors), and T674I/M-PDGFRalpha (clinically observed in hypereosinophilic syndrome). HG-7-85-01 is unique among all currently reported kinase inhibitors in having the ability to accommodate either a gatekeeper threonine, present in the wild-type forms of these kinases, or a large hydrophobic amino acid without becoming a promiscuous kinase inhibitor. The distinctive ability of HG-7-85-01 to simultaneously inhibit both wild-type and mutant forms of several kinases of clinical relevance is an important step in the development of the next generation of tyrosine kinase inhibitors.


  • Organizational Affiliation

    Department of Medical Oncology/Hematologic Neoplasia, Dana-Farber Cancer Institute, Boston, MA. Ellen_Weisberg@dfci.harvard.edu


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
PROTO-ONCOGENE TYROSINE-PROTEIN KINASE SRC
A, B
286Gallus gallusMutation(s): 0 
EC: 2.7.10.2
UniProt
Find proteins for P00523 (Gallus gallus)
Explore P00523 
Go to UniProtKB:  P00523
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00523
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free:  0.271 (Depositor), 0.270 (DCC) 
  • R-Value Work:  0.226 (Depositor), 0.230 (DCC) 
  • R-Value Observed: 0.230 (Depositor) 
Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.738α = 79.57
b = 61.393β = 89.1
c = 71.814γ = 90.14
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted NG7Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-02-15
    Type: Initial release
  • Version 1.1: 2019-02-27
    Changes: Data collection, Experimental preparation, Other
  • Version 1.2: 2021-04-28
    Changes: Data collection, Derived calculations, Other, Structure summary
  • Version 1.3: 2024-05-08
    Changes: Data collection, Database references