3ZMM

Inhibitors of Jak2 Kinase domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Novel Jak2-Stat Pathway Inhibitors with Extended Residence Time on Target.

Guan, H.Lamb, M.L.Peng, B.Huang, S.Degrace, N.Read, J.Hussain, S.Wu, J.Rivard, C.Alimzhanov, M.Bebernitz, G.Bell, K.Ye, M.Zinda, M.Ioannidis, S.

(2013) Bioorg Med Chem Lett 23: 3105

  • DOI: https://doi.org/10.1016/j.bmcl.2013.02.111
  • Primary Citation of Related Structures:  
    3ZMM

  • PubMed Abstract: 

    The discovery of the activating mutation V617F in the JH2 domain of Jak2 and the modulation of oncogenic Stat3 by Jak2 inhibitors have spurred a great interest in the inhibition of the Jak2/Stat pathway in oncology. In this Letter, we communicate the discovery of novel inhibitors of the Jak2/Stat5 axis, the N-(1H-pyrazol-3-yl)pyrimidin-2-amino derivatives. The rationale, synthesis and biological evaluation of these derivatives are reported. Two lead analogs from this series, 6 and 9, displayed prolonged residence time on Jak2, at enzymatic level. Although 6 and 9 exhibited moderate selectivity in a selected kinase panel, we chose to test these inhibitors in vivo as a consequence to their long residence time. However, extended inhibition of Jak2 due to the long residence time, in the form of inhibiting phosphorylation of downstream Stat5, was not recapitulated in an in vivo setting.


  • Organizational Affiliation

    Department of Cancer Chemistry, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.


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: 2.7.10.2 (PDB Primary Data), 2.7.1.112 (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
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
F9J PDBBind:  3ZMM Ki: 0.72 (nM) from 1 assay(s)
BindingDB:  3ZMM Ki: 0.72 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.193 
  • R-Value Observed: 0.195 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.506α = 90
b = 126.688β = 97.22
c = 135.593γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-04-17
    Type: Initial release
  • Version 1.1: 2013-05-08
    Changes: Database references, Source and taxonomy
  • Version 1.2: 2017-06-28
    Changes: Data collection
  • Version 1.3: 2023-12-20
    Changes: Advisory, Data collection, Database references, Derived calculations, Other, Refinement description