2XA4

Inhibitors of Jak2 Kinase domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.04 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of 5-Chloro-N2-[(1S)-1-(5-Fluoropyrimidin-2-Yl) Ethyl]-N4-(5-Methyl-1H-Pyrazol-3-Yl)Pyrimidine-2,4-Diamine (Azd1480) as a Novel Inhibitor of the Jak/Stat Pathway

Ioannidis, S.Lamb, M.L.Wang, T.Almeida, L.Block, M.H.Davies, A.M.Peng, B.Su, M.Zhang, H.Hoffmann, E.Rivard, C.Green, I.Howard, T.Pollard, H.Read, J.Alimzhanov, M.Bebernitz, G.Bell, K.Ye, M.Huszar, D.Zinda, M.

(2011) J Med Chem 54: 262

  • DOI: https://doi.org/10.1021/jm1011319
  • Primary Citation of Related Structures:  
    2XA4

  • PubMed Abstract: 

    The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.


  • Organizational Affiliation

    Department of Cancer Chemistry, AstraZeneca R&D, Boston, Massachusetts, United States. stephanos.ioannidis@astrazeneca.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): 2 
EC: 2.7.1.112 (PDB Primary Data), 2.7.10.2 (PDB Primary Data)
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
AZ5
Query on AZ5

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-CHLORO-N2-[(1S)-1-(5-FLUOROPYRIMIDIN-2-YL)ETHYL]-N4-(5-METHYL-1H-PYRAZOL-3-YL)PYRIMIDINE-2,4-DIAMINE
C14 H14 Cl F N8
PDOQBOJDRPLBQU-QMMMGPOBSA-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
AZ5 BindingDB:  2XA4 IC50: 58 (nM) from 1 assay(s)
Binding MOAD:  2XA4 IC50: 3 (nM) from 1 assay(s)
PDBBind:  2XA4 IC50: 3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.04 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.197 
  • R-Value Observed: 0.200 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 43.854α = 90
b = 126.741β = 97.04
c = 134.342γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-15
    Type: Initial release
  • Version 1.1: 2011-10-12
    Changes: Database references, Derived calculations, Refinement description, Version format compliance
  • Version 1.2: 2015-04-01
    Changes: Database references
  • Version 1.3: 2018-03-07
    Changes: Source and taxonomy
  • Version 1.4: 2019-05-08
    Changes: Data collection, Derived calculations, Experimental preparation