4PPC

ITK kinase domain with compound 27 (N-{1-[(1R)-3-(DIMETHYLAMINO)-1-PHENYLPROPYL]-1H-PYRAZOL-4-YL}-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.95 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.

Pastor, R.M.Burch, J.D.Magnuson, S.Ortwine, D.F.Chen, Y.De La Torre, K.Ding, X.Eigenbrot, C.Johnson, A.Liimatta, M.Liu, Y.Shia, S.Wang, X.Wu, L.C.Pei, Z.

(2014) Bioorg Med Chem Lett 24: 2448-2452

  • DOI: https://doi.org/10.1016/j.bmcl.2014.04.023
  • Primary Citation of Related Structures:  
    4PP9, 4PPA, 4PPB, 4PPC

  • PubMed Abstract: 

    There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.


  • Organizational Affiliation

    Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, United States. Electronic address: pastor.richard@gene.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK
A, B
266Homo 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
2VW
Query on 2VW

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
N-{1-[(1R)-3-(dimethylamino)-1-phenylpropyl]-1H-pyrazol-4-yl}-6-(1H-pyrazol-4-yl)-1H-indazole-3-carboxamide
C25 H26 N8 O
NCXHAHGMYXETMO-HSZRJFAPSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2VW BindingDB:  4PPC Ki: 0.93 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.95 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.456α = 90
b = 97.221β = 90
c = 134.806γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
BUSTERrefinement
XDSdata reduction
Aimlessdata 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: 2014-06-04
    Type: Initial release
  • Version 1.1: 2018-01-31
    Changes: Experimental preparation
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description