6NSL

CRYSTAL STRUCTURE OF TYROSINE KINASE 2 JH2 (PSEUDO KINASE DOMAIN) COMPLEXED WITH Compound-6c AKA 6-((1-(4-CYANOPHENY L)-2-OXO-1,2-DIHYDRO-3-PYRIDINYL)AMINO)-N-CYCLOPROPYL-8-(M ETHYLAMINO)IMIDAZO[1,2-B]PYRIDAZINE-3-CARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 
    0.213 (Depositor), 0.230 (DCC) 
  • R-Value Work: 
    0.202 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 
    0.203 (Depositor) 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted KZJClick on this verticalbar to view details

This is version 1.2 of the entry. See complete history


Literature

Identification of Imidazo[1,2-b]pyridazine Derivatives as Potent, Selective, and Orally Active Tyk2 JH2 Inhibitors.

Liu, C.Lin, J.Moslin, R.Tokarski, J.S.Muckelbauer, J.Chang, C.Tredup, J.Xie, D.Park, H.Li, P.Wu, D.R.Strnad, J.Zupa-Fernandez, A.Cheng, L.Chaudhry, C.Chen, J.Chen, C.Sun, H.Elzinga, P.D'arienzo, C.Gillooly, K.Taylor, T.L.McIntyre, K.W.Salter-Cid, L.Lombardo, L.J.Carter, P.H.Aranibar, N.Burke, J.R.Weinstein, D.S.

(2019) ACS Med Chem Lett 10: 383-388

  • DOI: https://doi.org/10.1021/acsmedchemlett.9b00035
  • Primary Citation of Related Structures:  
    6NSL

  • PubMed Abstract: 

    In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo- N 1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2- b ]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6 , which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.


  • Organizational Affiliation

    Research & Development, Bristol-Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Non-receptor tyrosine-protein kinase TYK2
A, B
317Homo sapiensMutation(s): 0 
Gene Names: TYK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P29597 (Homo sapiens)
Explore P29597 
Go to UniProtKB:  P29597
PHAROS:  P29597
GTEx:  ENSG00000105397 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP29597
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free:  0.213 (Depositor), 0.230 (DCC) 
  • R-Value Work:  0.202 (Depositor), 0.210 (DCC) 
  • R-Value Observed: 0.203 (Depositor) 
Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 70.015α = 90
b = 65.654β = 112.7
c = 74.68γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted KZJClick on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-01-29
    Type: Initial release
  • Version 1.1: 2020-04-15
    Changes: Database references
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references