3KFA

Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.22 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural analysis of DFG-in and DFG-out dual Src-Abl inhibitors sharing a common vinyl purine template.

Zhou, T.Commodore, L.Huang, W.S.Wang, Y.Sawyer, T.K.Shakespeare, W.C.Clackson, T.Zhu, X.Dalgarno, D.C.

(2010) Chem Biol Drug Des 75: 18-28

  • DOI: https://doi.org/10.1111/j.1747-0285.2009.00905.x
  • Primary Citation of Related Structures:  
    3KF4, 3KFA

  • PubMed Abstract: 

    Bcr-Abl is the oncogenic protein tyrosine kinase responsible for chronic myeloid leukemia (CML). Treatment of the disease with imatinib (Gleevec) often results in drug resistance via kinase mutations at the advanced phases of the disease, which has necessitated the development of new mutation-resistant inhibitors, notably against the T315I gatekeeper mutation. As part of our efforts to discover such mutation resistant Abl inhibitors, we have focused on optimizing purine template kinase inhibitors, leading to the discovery of potent DFG-in and DFG-out series of Abl inhibitors that are also potent Src inhibitors. Here we present crystal structures of Abl bound by two such inhibitors, based on a common N9-arenyl purine, and that represent both DFG-in and -out binding modes. In each structure the purine template is bound deeply in the adenine pocket and the novel vinyl linker forms a non-classical hydrogen bond to the gatekeeper residue, Thr315. Specific template substitutions promote either a DFG-in or -out binding mode, with the kinase binding site adjusting to optimize molecular recognition. Bcr-Abl T315I mutant kinase is resistant to all currently marketed Abl inhibitors, and is the focus of intense drug discovery efforts. Notably, our DFG-out inhibitor, AP24163, exhibits modest activity against this mutant, illustrating that this kinase mutant can be inhibited by DFG-out class inhibitors. Furthermore our DFG-out inhibitor exhibits dual Src-Abl activity, absent from the prototypical DFG-out inhibitor, imatinib as well as its analog, nilotinib. The data presented here provides structural guidance for the further design of novel potent DFG-out class inhibitors against Src, Abl and Abl T315I mutant kinases.


  • Organizational Affiliation

    ARIAD Pharmaceuticals Inc, 26 Landsdowne St., Cambridge, MA 02139, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1
A, B
288Mus musculusMutation(s): 0 
Gene Names: AblAbl1c-Abl
EC: 2.7.10.2
UniProt
Find proteins for P00520 (Mus musculus)
Explore P00520 
Go to UniProtKB:  P00520
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00520
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
B91
Query on B91

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
3-{(E)-2-[6-(cyclopropylamino)-9H-purin-9-yl]ethenyl}-4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]benzamide
C29 H25 F3 N8 O
XQBYDVRVYRYLCH-BQYQJAHWSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
B91 PDBBind:  3KFA IC50: 25 (nM) from 1 assay(s)
BindingDB:  3KFA IC50: min: 25, max: 2.50e+4 (nM) from 3 assay(s)
Binding MOAD:  3KFA IC50: 25 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.22 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.201 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.47α = 90
b = 59.98β = 89.99
c = 123.55γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
CNSrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-12-22 
  • Deposition Author(s): Zhou, T.

Revision History  (Full details and data files)

  • Version 1.0: 2009-12-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description