5TQ5

Design and Synthesis of a pan-JAK Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.332 
  • R-Value Work: 0.279 
  • R-Value Observed: 0.282 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin.

Jones, P.Storer, R.I.Sabnis, Y.A.Wakenhut, F.M.Whitlock, G.A.England, K.S.Mukaiyama, T.Dehnhardt, C.M.Coe, J.W.Kortum, S.W.Chrencik, J.E.Brown, D.G.Jones, R.M.Murphy, J.R.Yeoh, T.Morgan, P.Kilty, I.

(2017) J Med Chem 60: 767-786

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01634
  • Primary Citation of Related Structures:  
    5TQ3, 5TQ4, 5TQ5, 5TQ6, 5TQ7, 5TQ8

  • PubMed Abstract: 

    By use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies.


  • Organizational Affiliation

    Medicine Design, ‡Pharmacokinetics, Dynamics and Metabolism, and §Inflammation and Immunology Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2298Homo sapiensMutation(s): 2 
Gene Names: JAK2
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
7GX
Query on 7GX

Download Ideal Coordinates CCD File 
B [auth A]6-(2-ethyl-4-hydroxyphenyl)-N-(6-methylpyridin-3-yl)-1H-indazole-3-carboxamide
C22 H20 N4 O2
CUKXYSDQFPFABZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
7GX BindingDB:  5TQ5 IC50: 59 (nM) from 1 assay(s)
Binding MOAD:  5TQ5 IC50: 58.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.332 
  • R-Value Work: 0.279 
  • R-Value Observed: 0.282 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.997α = 104.11
b = 45.106β = 110.08
c = 52.807γ = 94.73
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata 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: 2017-01-11
    Type: Initial release
  • Version 1.1: 2017-01-18
    Changes: Database references
  • Version 1.2: 2017-02-08
    Changes: Database references
  • Version 1.3: 2018-04-18
    Changes: Data collection
  • Version 1.4: 2024-03-06
    Changes: Data collection, Database references