4HCT

Crystal structure of ITK in complex with compound 52


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.48 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay.

Zapf, C.W.Gerstenberger, B.S.Xing, L.Limburg, D.C.Anderson, D.R.Caspers, N.Han, S.Aulabaugh, A.Kurumbail, R.Shakya, S.Li, X.Spaulding, V.Czerwinski, R.M.Seth, N.Medley, Q.G.

(2012) J Med Chem 55: 10047-10063

  • DOI: https://doi.org/10.1021/jm301190s
  • Primary Citation of Related Structures:  
    4HCT, 4HCU, 4HCV

  • PubMed Abstract: 

    We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half-lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half-life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk.


  • Organizational Affiliation

    BioTherapeutics Chemistry, Pfizer Worldwide Medicinal Chemistry, 200 Cambridgepark Drive, Cambridge, Massachusetts 02140, USA. christoph.zapf@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK269Homo sapiensMutation(s): 1 
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
18R
Query on 18R

Download Ideal Coordinates CCD File 
B [auth A]3-{1-[(3R)-1-acryloylpiperidin-3-yl]-4-amino-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-(3-tert-butylphenyl)benzamide
C30 H33 N7 O2
RMAUIYTVKFMOGP-HSZRJFAPSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
18R PDBBind:  4HCT IC50: 73 (nM) from 1 assay(s)
BindingDB:  4HCT IC50: min: 10, max: 2210 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.48 Å
  • R-Value Free: 0.184 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.172 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.41α = 90
b = 67.85β = 111.23
c = 49.28γ = 90
Software Package:
Software NamePurpose
autoPROCdata collection
BUSTERrefinement
autoPROCdata scaling
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-14
    Type: Initial release
  • Version 1.1: 2013-01-02
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Refinement description