4AQC

Triazolopyridine-based Inhibitor of Janus Kinase 2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Selective, Orally Bioavailable 1,2,4-Triazolo[1,5-A]Pyridine-Based Inhibitor of Janus Kinase 2 for Use in Anticancer Therapy: Discovery of Cep-33779.

Dugan, B.J.Gingrich, D.E.Mesaros, E.F.Milkiewicz, K.L.Curry, M.A.Zulli, A.L.Dobrzanski, P.Serdikoff, C.Jan, M.Angeles, T.S.Albom, M.S.Mason, J.L.Aimone, L.D.Meyer, S.L.Huang, Z.Wells-Knecht, K.J.Ator, M.A.Ruggeri, B.A.Dorsey, B.D.

(2012) J Med Chem 55: 5243

  • DOI: https://doi.org/10.1021/jm300248q
  • Primary Citation of Related Structures:  
    4AQC

  • PubMed Abstract: 

    Members of the JAK family of nonreceptor tyrosine kinases play a critical role in the growth and progression of many cancers and in inflammatory diseases. JAK2 has emerged as a leading therapeutic target for oncology, providing a rationale for the development of a selective JAK2 inhibitor. A program to optimize selective JAK2 inhibitors to combat cancer while reducing the risk of immune suppression associated with JAK3 inhibition was undertaken. The structure-activity relationships and biological evaluation of a novel series of compounds based on a 1,2,4-triazolo[1,5-a]pyridine scaffold are reported. Para substitution on the aryl at the C8 position of the core was optimum for JAK2 potency (17). Substitution at the C2 nitrogen position was required for cell potency (21). Interestingly, meta substitution of C2-NH-aryl moiety provided exceptional selectivity for JAK2 over JAK3 (23). These efforts led to the discovery of CEP-33779 (29), a novel, selective, and orally bioavailable inhibitor of JAK2.


  • Organizational Affiliation

    Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, Pennsylvania 19380, United States. bdugan@cephalon.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
TYROSINE-PROTEIN KINASE JAK2
A, B
301Homo sapiensMutation(s): 0 
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
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
88A BindingDB:  4AQC IC50: min: 0.9, max: 61 (nM) from 2 assay(s)
Binding MOAD:  4AQC IC50: 0.9 (nM) from 1 assay(s)
PDBBind:  4AQC IC50: 0.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.217 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.178 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.679α = 90
b = 111.679β = 90
c = 70.422γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-04-25
    Type: Initial release
  • Version 1.1: 2012-06-27
    Changes: Other
  • Version 1.2: 2019-05-08
    Changes: Data collection, Derived calculations, Experimental preparation, Other