4PQN

ITK kinase domain with compound GNE-9822


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Property- and structure-guided discovery of a tetrahydroindazole series of interleukin-2 inducible T-cell kinase inhibitors.

Burch, J.D.Lau, K.Barker, J.J.Brookfield, F.Chen, Y.Chen, Y.Eigenbrot, C.Ellebrandt, C.Ismaili, M.H.Johnson, A.Kordt, D.MacKinnon, C.H.McEwan, P.A.Ortwine, D.F.Stein, D.B.Wang, X.Winkler, D.Yuen, P.W.Zhang, Y.Zarrin, A.A.Pei, Z.

(2014) J Med Chem 57: 5714-5727

  • DOI: https://doi.org/10.1021/jm500550e
  • Primary Citation of Related Structures:  
    4PQN, 4PRJ

  • PubMed Abstract: 

    Interleukin-2 inducible T-cell kinase (ITK), a member of the Tec family of tyrosine kinases, plays a major role in T-cell signaling downstream of the T-cell receptor (TCR), and considerable efforts have been directed toward discovery of ITK-selective inhibitors as potential treatments of inflammatory disorders such as asthma. Using a previously disclosed indazole series of inhibitors as a starting point, and using X-ray crystallography and solubility forecast index (SFI) as guides, we evolved a series of tetrahydroindazole inhibitors with improved potency, selectivity, and pharmaceutical properties. Highlights include identification of a selectivity pocket above the ligand plane, and identification of appropriate lipophilic substituents to occupy this space. This effort culminated in identification of a potent and selective ITK inhibitor (GNE-9822) with good ADME properties in preclinical species.


  • Organizational Affiliation

    Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK266Homo sapiensMutation(s): 3 
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
2W6
Query on 2W6

Download Ideal Coordinates CCD File 
B [auth A]N-{1-[(1S)-3-(dimethylamino)-1-phenylpropyl]-1H-pyrazol-4-yl}-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxamide
C24 H32 N6 O
XFYUTGIEFKGWND-NRFANRHFSA-N
P4G
Query on P4G

Download Ideal Coordinates CCD File 
C [auth A]1-ETHOXY-2-(2-ETHOXYETHOXY)ETHANE
C8 H18 O3
RRQYJINTUHWNHW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2W6 Binding MOAD:  4PQN Ki: 0.7 (nM) from 1 assay(s)
BindingDB:  4PQN Ki: 0.7 (nM) from 1 assay(s)
IC50: min: 45, max: 55 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.202 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 120.18α = 90
b = 39.03β = 93.07
c = 50.68γ = 90
Software Package:
Software NamePurpose
GDAdata collection
PHASERphasing
REFMACrefinement
XDSdata reduction
SCALAdata 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: 2014-07-02
    Type: Initial release
  • Version 1.1: 2014-07-23
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description