6N7B

Structure of the human JAK1 kinase domain with compound 38


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling.

Zak, M.Hanan, E.J.Lupardus, P.Brown, D.G.Robinson, C.Siu, M.Lyssikatos, J.P.Romero, F.A.Zhao, G.Kellar, T.Mendonca, R.Ray, N.C.Goodacre, S.C.Crackett, P.H.McLean, N.Hurley, C.A.Yuen, P.W.Cheng, Y.X.Liu, X.Liimatta, M.Kohli, P.B.Nonomiya, J.Salmon, G.Buckley, G.Lloyd, J.Gibbons, P.Ghilardi, N.Kenny, J.R.Johnson, A.

(2019) Bioorg Med Chem Lett 29: 1522-1531

  • DOI: https://doi.org/10.1016/j.bmcl.2019.04.008
  • Primary Citation of Related Structures:  
    6N77, 6N78, 6N79, 6N7A, 6N7B, 6N7C, 6N7D

  • PubMed Abstract: 

    Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC 50 's in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).


  • Organizational Affiliation

    Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: mzak@gene.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK1302Homo 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
KEY
Query on KEY

Download Ideal Coordinates CCD File 
B [auth A]N-[3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl]-1H-pyrazolo[4,3-c]pyridine-7-carboxamide
C18 H15 Cl N6 O2
NBFASNUBTMTAFQ-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
KEY Binding MOAD:  6N7B Ki: 0.6 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.81 Å
  • R-Value Free: 0.264 
  • R-Value Work: 0.220 
  • R-Value Observed: 0.222 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 170.285α = 90
b = 42.788β = 90
c = 44.986γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
xia2data reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-04-24
    Type: Initial release
  • Version 1.1: 2019-05-15
    Changes: Data collection, Database references