4IVB

JAK1 kinase (JH1 domain) in complex with the inhibitor TRANS-4-{2-[(1R)-1-HYDROXYETHYL]IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL}CYCLOHEXANECARBONITRILE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.

Zak, M.Hurley, C.A.Ward, S.I.Bergeron, P.Barrett, K.Balazs, M.Blair, W.S.Bull, R.Chakravarty, P.Chang, C.Crackett, P.Deshmukh, G.Devoss, J.Dragovich, P.S.Eigenbrot, C.Ellwood, C.Gaines, S.Ghilardi, N.Gibbons, P.Gradl, S.Gribling, P.Hamman, C.Harstad, E.Hewitt, P.Johnson, A.Johnson, T.Kenny, J.R.Koehler, M.F.Bir Kohli, P.Labadie, S.Lee, W.P.Liao, J.Liimatta, M.Mendonca, R.Narukulla, R.Pulk, R.Reeve, A.Savage, S.Shia, S.Steffek, M.Ubhayakar, S.van Abbema, A.Aliagas, I.Avitabile-Woo, B.Xiao, Y.Yang, J.Kulagowski, J.J.

(2013) J Med Chem 56: 4764-4785

  • DOI: https://doi.org/10.1021/jm4004895
  • Primary Citation of Related Structures:  
    4IVA, 4IVB, 4IVC, 4IVD

  • PubMed Abstract: 

    Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.


  • Organizational Affiliation

    Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 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
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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1J5
Query on 1J5

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
trans-4-{2-[(1R)-1-hydroxyethyl]imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl}cyclohexanecarbonitrile
C17 H19 N5 O
ANDWOIMHOOWCLK-IJLUTSLNSA-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
1J5 PDBBind:  4IVB Ki: 1.9 (nM) from 1 assay(s)
BindingDB:  4IVB Ki: 1.9 (nM) from 1 assay(s)
EC50: min: 120, max: 130 (nM) from 2 assay(s)
Binding MOAD:  4IVB Ki: 1.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.221 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 42.918α = 90
b = 173.479β = 94.29
c = 44.54γ = 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: 2013-05-22
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-12-06
    Changes: Data collection