4F08

Discovery and Optimization of C-2 Methyl Imidazo-pyrrolopyridines as Potent and Orally Bioavailable JAK1 Inhibitors with Selectivity over JAK2


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.82 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 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 JAK2
A, B
302Homo sapiensMutation(s): 0 
Gene Names: JAK2JAK2 kinase domain
EC: 2.7.10.2
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
1RS
Query on 1RS

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
1-(piperidin-4-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine
C13 H15 N5
VTICMARMQUNXBS-UHFFFAOYSA-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
1RS BindingDB:  4F08 Ki: 250 (nM) from 1 assay(s)
EC50: 8800 (nM) from 1 assay(s)
JAK PDBBind:  4F08 Ki: 250 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.82 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.214 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 110.923α = 90
b = 110.923β = 90
c = 70.732γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-07-04 
  • Deposition Author(s): Murray, J.M.

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-04
    Type: Initial release
  • Version 1.1: 2012-07-25
    Changes: Database references
  • Version 1.2: 2013-05-29
    Changes: Non-polymer description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2023-12-06
    Changes: Data collection