4EHZ

The Jak1 kinase domain in complex with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.17 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery and optimization of C-2 methyl imidazopyrrolopyridines as potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2.

Zak, M.Mendonca, R.Balazs, M.Barrett, K.Bergeron, P.Blair, W.S.Chang, C.Deshmukh, G.Devoss, J.Dragovich, P.S.Eigenbrot, C.Ghilardi, N.Gibbons, P.Gradl, S.Hamman, C.Hanan, E.J.Harstad, E.Hewitt, P.R.Hurley, C.A.Jin, T.Johnson, A.Johnson, T.Kenny, J.R.Koehler, M.F.Bir Kohli, P.Kulagowski, J.J.Labadie, S.Liao, J.Liimatta, M.Lin, Z.Lupardus, P.J.Maxey, R.J.Murray, J.M.Pulk, R.Rodriguez, M.Savage, S.Shia, S.Steffek, M.Ubhayakar, S.Ultsch, M.van Abbema, A.Ward, S.I.Xiao, L.Xiao, Y.

(2012) J Med Chem 55: 6176-6193

  • DOI: https://doi.org/10.1021/jm300628c
  • Primary Citation of Related Structures:  
    4EHZ, 4EI4, 4F08, 4F09

  • PubMed Abstract: 

    Herein we report the discovery of the C-2 methyl substituted imidazopyrrolopyridine series and its optimization to provide potent and orally bioavailable JAK1 inhibitors with selectivity over JAK2. The C-2 methyl substituted inhibitor 4 exhibited not only improved JAK1 potency relative to unsubstituted compound 3 but also notable JAK1 vs JAK2 selectivity (20-fold and >33-fold in biochemical and cell-based assays, respectively). Features of the X-ray structures of 4 in complex with both JAK1 and JAK2 are delineated. Efforts to improve the in vitro and in vivo ADME properties of 4 while maintaining JAK1 selectivity are described, culminating in the discovery of a highly optimized and balanced inhibitor (20). Details of the biological characterization of 20 are disclosed including JAK1 vs JAK2 selectivity levels, preclinical in vivo PK profiles, performance in an in vivo JAK1-mediated PK/PD model, and attributes of an X-ray structure in complex with JAK1.


  • Organizational Affiliation

    Department of Discovery Chemistry, Genentech, Inc, South San Francisco, CA 94080, USA. mzak@gene.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK1
A, B, C, 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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
JAK
Query on JAK

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B],
M [auth C],
R [auth D]
2-methyl-1-(piperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine
C14 H17 N5
XTQACRIFOIASKV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [auth A]
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
L [auth B],
N [auth C],
O [auth C],
P [auth C],
Q [auth C],
S [auth D],
T [auth D]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B, C, D
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
JAK PDBBind:  4EHZ Ki: 10 (nM) from 1 assay(s)
BindingDB:  4EHZ Ki: 10 (nM) from 1 assay(s)
EC50: 250 (nM) from 1 assay(s)
Binding MOAD:  4EHZ Ki: 10 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.17 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.712α = 90
b = 172.175β = 92.28
c = 88.035γ = 90
Software Package:
Software NamePurpose
BOSdata collection
PHASERphasing
PHENIXrefinement
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: 2012-07-04
    Type: Initial release
  • Version 1.1: 2012-08-29
    Changes: Database references
  • Version 1.2: 2013-01-23
    Changes: Database references