4AGW

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 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.230 

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Ligand Structure Quality Assessment 


This is version 1.2 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
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.230 
  • 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

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Ligand Structure Quality Assessment 


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