5CY3

SYK catalytic domain complexed with a potent and orally bioavailable benzisothiazole inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Orally bioavailable Syk inhibitors with activity in a rat PK/PD model.

Thoma, G.Veenstra, S.Strang, R.Blanz, J.Vangrevelinghe, E.Berghausen, J.Lee, C.C.Zerwes, H.G.

(2015) Bioorg Med Chem Lett 25: 4642-4647

  • DOI: https://doi.org/10.1016/j.bmcl.2015.08.037
  • Primary Citation of Related Structures:  
    5CXH, 5CXZ, 5CY3

  • PubMed Abstract: 

    Design and optimization of benzo- and pyrido-thiazoles/isothiazoles are reported leading to the discovery of the potent, orally bioavailable Syk inhibitor 5, which was found to be active in a rat PK/PD model. Compound 5 showed acceptable overall kinase selectivity. However, in addition to Syk it also inhibited Aurora kinase in enzymatic and cellular settings leading to findings in the micronucleus assay. As a consequence, compound 5 was not further pursued.


  • Organizational Affiliation

    Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland. Electronic address: gebhard.thoma@novartis.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase SYK291Homo sapiensMutation(s): 1 
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
55Y
Query on 55Y

Download Ideal Coordinates CCD File 
B [auth A](5R)-5-[(1R)-1-{[6-(1-methyl-1H-pyrazol-4-yl)-2,1-benzothiazol-4-yl]oxy}ethyl]-1,3-oxazolidin-2-one
C16 H16 N4 O3 S
MKTGBKHCRFUALQ-RFAUZJTJSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
55Y BindingDB:  5CY3 IC50: min: 16, max: 737 (nM) from 3 assay(s)
Binding MOAD:  5CY3 IC50: 16 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.76 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.171 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.504α = 90
b = 37.656β = 100.14
c = 90.888γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-09-23 
  • Deposition Author(s): Lee, C.C.

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-23
    Type: Initial release
  • Version 1.1: 2015-10-28
    Changes: Database references
  • Version 1.2: 2015-12-16
    Changes: Refinement description
  • Version 1.3: 2024-03-06
    Changes: Data collection, Database references, Derived calculations