3QGY

Crystal structure of ITK inhibitor complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.208 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors

Charrier, J.D.Miller, A.Kay, D.P.Brenchley, G.Twin, H.C.Collier, P.N.Ramaya, S.Keily, S.B.Durrant, S.J.Knegtel, R.M.Tanner, A.J.Brown, K.Curnock, A.P.Jimenez, J.M.

(2011) J Med Chem 54: 2341-2350

  • DOI: https://doi.org/10.1021/jm101499u
  • Primary Citation of Related Structures:  
    3QGW, 3QGY

  • PubMed Abstract: 

    Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.


  • Organizational Affiliation

    Department of Chemistry, Vertex Pharmaceuticals (Europe) Ltd., 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK. jean-damien_charrier@vrtx.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ITK/TSK
A, B
286Homo sapiensMutation(s): 0 
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
PQC
Query on PQC

Download Ideal Coordinates CCD File 
C [auth A]3-[(8-phenylthieno[2,3-h]quinazolin-2-yl)amino]benzenesulfonamide
C22 H16 N4 O2 S2
ZSSGEBJSMMYEMX-UHFFFAOYSA-N
L7O
Query on L7O

Download Ideal Coordinates CCD File 
D [auth B]N-{5-[2-(methylamino)pyrimidin-4-yl]-2-oxo-1,2-dihydropyridin-3-yl}-4-(piperidin-1-yl)benzamide
C22 H24 N6 O2
MKSQDWBNZVGINB-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
L7O Binding MOAD:  3QGY Ki: 16 (nM) from 1 assay(s)
BindingDB:  3QGY Ki: 16 (nM) from 1 assay(s)
PDBBind:  3QGY Ki: 16 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.208 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 125.8601α = 90
b = 74.3809β = 93.9867
c = 78.833γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
AMoREphasing
CNSrefinement
MOSFLMdata 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: 2011-06-22
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-03-20
    Changes: Data collection, Database references, Derived calculations