4YTC

Discovery of VX-509 (Decernotinib): A Potent and Selective Janus kinase (JAK) 3 Inhibitor for the Treatment of Autoimmune Disease


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.16 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of VX-509 (Decernotinib): A Potent and Selective Janus Kinase 3 Inhibitor for the Treatment of Autoimmune Diseases.

Farmer, L.J.Ledeboer, M.W.Hoock, T.Arnost, M.J.Bethiel, R.S.Bennani, Y.L.Black, J.J.Brummel, C.L.Chakilam, A.Dorsch, W.A.Fan, B.Cochran, J.E.Halas, S.Harrington, E.M.Hogan, J.K.Howe, D.Huang, H.Jacobs, D.H.Laitinen, L.M.Liao, S.Mahajan, S.Marone, V.Martinez-Botella, G.McCarthy, P.Messersmith, D.Namchuk, M.Oh, L.Penney, M.S.Pierce, A.C.Raybuck, S.A.Rugg, A.Salituro, F.G.Saxena, K.Shannon, D.Shlyakter, D.Swenson, L.Tian, S.K.Town, C.Wang, J.Wang, T.Wannamaker, M.W.Winquist, R.J.Zuccola, H.J.

(2015) J Med Chem 58: 7195-7216

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b00301
  • Primary Citation of Related Structures:  
    4YTC, 4YTF, 4YTH, 4YTI

  • PubMed Abstract: 

    While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). On the basis of these findings, it appears that VX-509 offers potential for the treatment of a variety of autoimmune diseases.


  • Organizational Affiliation

    Vertex Pharmaceuticals (Canada) Inc. , 275 Armand-Frappier, Laval, Québec H7V 4A7, Canada.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2296Homo sapiensMutation(s): 0 
Gene Names: JAK2
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for O60674 (Homo sapiens)
Explore O60674 
Go to UniProtKB:  O60674
PHAROS:  O60674
GTEx:  ENSG00000096968 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60674
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4HW
Query on 4HW

Download Ideal Coordinates CCD File 
B [auth A]N~3~-phenyl-1-[6-(phenylamino)pyrimidin-4-yl]-1H-1,2,4-triazole-3,5-diamine
C18 H16 N8
PYFLNUFSEAXOHE-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.16 Å
  • R-Value Free: 0.213 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 94.569α = 90
b = 101.516β = 90
c = 68.377γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
BUSTERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2015-08-19
    Changes: Other
  • Version 1.2: 2015-09-23
    Changes: Database references
  • Version 1.3: 2015-10-07
    Changes: Database references