3T9T

Crystal structure of BTK mutant (F435T,K596R) complexed with Imidazo[1,5-a]quinoxaline


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Imidazo[1,5-a]quinoxalines as irreversible BTK inhibitors for the treatment of rheumatoid arthritis.

Kim, K.H.Maderna, A.Schnute, M.E.Hegen, M.Mohan, S.Miyashiro, J.Lin, L.Li, E.Keegan, S.Lussier, J.Wrocklage, C.Nickerson-Nutter, C.L.Wittwer, A.J.Soutter, H.Caspers, N.Han, S.Kurumbail, R.Dunussi-Joannopoulos, K.Douhan, J.Wissner, A.

(2011) Bioorg Med Chem Lett 21: 6258-6263

  • DOI: https://doi.org/10.1016/j.bmcl.2011.09.008
  • Primary Citation of Related Structures:  
    3T9T

  • PubMed Abstract: 

    Imidazo[1,5-a]quinoxalines were synthesized that function as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The syntheses and SAR of this series of compounds are presented as well as the X-ray crystal structure of the lead compound 36 in complex with a gate-keeper variant of ITK enzyme. The lead compound showed good in vivo efficacy in preclinical RA models.


  • Organizational Affiliation

    Medicinal Chemistry, Pfizer, 200 Cambridge Park Drive, Cambridge, MA 02140, United States. khkim87@hotmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK267Homo sapiensMutation(s): 2 
Gene Names: ITKEMTLYK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q08881 (Homo sapiens)
Explore Q08881 
Go to UniProtKB:  Q08881
PHAROS:  Q08881
GTEx:  ENSG00000113263 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08881
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IAQ
Query on IAQ

Download Ideal Coordinates CCD File 
B [auth A](2Z)-4-(dimethylamino)-N-{7-fluoro-4-[(2-methylphenyl)amino]imidazo[1,5-a]quinoxalin-8-yl}-N-methylbut-2-enamide
C24 H25 F N6 O
YMSXHRWUGLAAKL-YFHOEESVSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
IAQ PDBBind:  3T9T IC50: 1.93 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.34α = 90
b = 69.35β = 115.7
c = 47.27γ = 90
Software Package:
Software NamePurpose
autoPROCdata collection
PHASERphasing
REFMACrefinement
autoPROCdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-12
    Type: Initial release
  • Version 1.1: 2011-10-26
    Changes: Database references
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references, Derived calculations, Refinement description