4E4L

JAK1 kinase (JH1 domain) in complex with compound 30


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors.

Kulagowski, J.J.Blair, W.Bull, R.J.Chang, C.Deshmukh, G.Dyke, H.J.Eigenbrot, C.Ghilardi, N.Gibbons, P.Harrison, T.K.Hewitt, P.R.Liimatta, M.Hurley, C.A.Johnson, A.Johnson, T.Kenny, J.R.Bir Kohli, P.Maxey, R.J.Mendonca, R.Mortara, K.Murray, J.Narukulla, R.Shia, S.Steffek, M.Ubhayakar, S.Ultsch, M.van Abbema, A.Ward, S.I.Waszkowycz, B.Zak, M.

(2012) J Med Chem 55: 5901-5921

  • DOI: https://doi.org/10.1021/jm300438j
  • Primary Citation of Related Structures:  
    4E4L, 4E4M, 4E4N, 4E5W, 4E6D, 4E6Q

  • PubMed Abstract: 

    A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Argenta, 8/9 Spire Green Centre, Harlow CM19 5TR, United Kingdom. janusz.kulagowski@glpg


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK1A,
B,
C [auth E],
D
302Homo sapiensMutation(s): 0 
Gene Names: JAK1JAK1AJAK1B
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P23458 (Homo sapiens)
Explore P23458 
Go to UniProtKB:  P23458
PHAROS:  P23458
GTEx:  ENSG00000162434 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23458
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A,
B,
C [auth E],
D
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
0NH Binding MOAD:  4E4L Ki: 1.7 (nM) from 1 assay(s)
BindingDB:  4E4L Ki: 1.7 (nM) from 1 assay(s)
EC50: 210 (nM) from 1 assay(s)
PDBBind:  4E4L Ki: 1.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.191 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.837α = 90
b = 171.759β = 92.15
c = 87.821γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-05-30
    Type: Initial release
  • Version 1.1: 2012-07-11
    Changes: Database references