3TJD

co-crystal structure of Jak2 with thienopyridine 19


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.312 
  • R-Value Work: 0.286 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Discovery of potent and highly selective thienopyridine janus kinase 2 inhibitors.

Schenkel, L.B.Huang, X.Cheng, A.Deak, H.L.Doherty, E.Emkey, R.Gu, Y.Gunaydin, H.Kim, J.L.Lee, J.Loberg, R.Olivieri, P.Pistillo, J.Tang, J.Wan, Q.Wang, H.L.Wang, S.W.Wells, M.C.Wu, B.Yu, V.Liu, L.Geuns-Meyer, S.

(2011) J Med Chem 54: 8440-8450

  • DOI: https://doi.org/10.1021/jm200911r
  • Primary Citation of Related Structures:  
    3TJC, 3TJD

  • PubMed Abstract: 

    Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Amgen, Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA. laurie.schenkel@amgen.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2
A, B
298Homo 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
6TP
Query on 6TP

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-amino-2-[4-(tert-butylsulfamoyl)phenyl]-N-methylthieno[3,2-c]pyridine-7-carboxamide
C19 H22 N4 O3 S2
FVVCSMCEMMLEGG-UHFFFAOYSA-N
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
6TP BindingDB:  3TJD IC50: min: 1, max: 1480 (nM) from 4 assay(s)
PDBBind:  3TJD IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.90 Å
  • R-Value Free: 0.312 
  • R-Value Work: 0.286 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 111.82α = 90
b = 111.82β = 90
c = 71.12γ = 90
Software Package:
Software NamePurpose
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2011-11-30 
  • Deposition Author(s): Huang, X.

Revision History  (Full details and data files)

  • Version 1.0: 2011-11-30
    Type: Initial release
  • Version 1.1: 2011-12-28
    Changes: Database references