4I0T

Crystal structure of spleen tyrosine kinase complexed with 2-(5,6,7,8-Tetrahydro-imidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.236 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Pyrrolopyrazines as selective spleen tyrosine kinase inhibitors.

Padilla, F.Bhagirath, N.Chen, S.Chiao, E.Goldstein, D.M.Hermann, J.C.Hsu, J.Kennedy-Smith, J.J.Kuglstatter, A.Liao, C.Liu, W.Lowrie, L.E.Luk, K.C.Lynch, S.M.Menke, J.Niu, L.Owens, T.D.O-Yang, C.Railkar, A.Schoenfeld, R.C.Slade, M.Steiner, S.Tan, Y.C.Villasenor, A.G.Wang, C.Wanner, J.Xie, W.Xu, D.Zhang, X.Zhou, M.Lucas, M.C.

(2013) J Med Chem 56: 1677-1692

  • DOI: https://doi.org/10.1021/jm301720p
  • Primary Citation of Related Structures:  
    4I0R, 4I0S, 4I0T

  • PubMed Abstract: 

    We describe the discovery of several pyrrolopyrazines as potent and selective Syk inhibitors and the efforts that eventually led to the desired improvements in physicochemical properties and human whole blood potencies. Ultimately, our mouse model revealed unexpected toxicity that precluded us from further advancing this series.


  • Organizational Affiliation

    Hoffmann-La Roche Inc., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley, New Jersey 07110, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase SYK291Homo sapiensMutation(s): 0 
Gene Names: SYK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P43405 (Homo sapiens)
Explore P43405 
Go to UniProtKB:  P43405
PHAROS:  P43405
GTEx:  ENSG00000165025 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP43405
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1B6
Query on 1B6

Download Ideal Coordinates CCD File 
B [auth A]N-tert-butyl-2-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide
C18 H22 N6 O
NEVNJCLJFXHCCC-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1B6 BindingDB:  4I0T IC50: min: 26, max: 634 (nM) from 3 assay(s)
Binding MOAD:  4I0T IC50: 26 (nM) from 1 assay(s)
PDBBind:  4I0T IC50: 26 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.268 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.236 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.854α = 90
b = 87.405β = 90
c = 88.867γ = 90
Software Package:
Software NamePurpose
MAR345data collection
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-10-30
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description