4GFM

JAK2 kinase (JH1 domain) with 2,6-DICHLORO-N-(2-OXO-2,5-DIHYDROPYRIDIN-4-YL)BENZAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Lead identification of novel and selective TYK2 inhibitors.

Liang, J.Tsui, V.Van Abbema, A.Bao, L.Barrett, K.Beresini, M.Berezhkovskiy, L.Blair, W.S.Chang, C.Driscoll, J.Eigenbrot, C.Ghilardi, N.Gibbons, P.Halladay, J.Johnson, A.Kohli, P.B.Lai, Y.Liimatta, M.Mantik, P.Menghrajani, K.Murray, J.Sambrone, A.Xiao, Y.Shia, S.Shin, Y.Smith, J.Sohn, S.Stanley, M.Ultsch, M.Zhang, B.Wu, L.C.Magnuson, S.

(2013) Eur J Med Chem 67: 175-187

  • DOI: https://doi.org/10.1016/j.ejmech.2013.03.070
  • Primary Citation of Related Structures:  
    4GFM, 4GFO, 4GIH, 4GMY, 4GVJ

  • PubMed Abstract: 

    A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as psoriasis and inflammatory bowel diseases (IBD), by selective targeting of TYK2. Hit triage, following a high-throughput screen for TYK2 inhibitors, revealed pyridine 1 as a promising starting point for lead identification. Initial expansion of 3 separate regions of the molecule led to eventual identification of cyclopropyl amide 46, a potent lead analog with good kinase selectivity, physicochemical properties, and pharmacokinetic profile. Analysis of the binding modes of the series in TYK2 and JAK2 crystal structures revealed key interactions leading to good TYK2 potency and design options for future optimization of selectivity.


  • Organizational Affiliation

    Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase JAK2302Homo sapiensMutation(s): 0 
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
0X2
Query on 0X2

Download Ideal Coordinates CCD File 
B [auth A]2,6-dichloro-N-(2-oxo-2,5-dihydropyridin-4-yl)benzamide
C12 H8 Cl2 N2 O2
HKIJJBMBTHKEPC-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
0X2 Binding MOAD:  4GFM Ki: 60 (nM) from 1 assay(s)
PDBBind:  4GFM Ki: 60 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.171 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 93.094α = 90
b = 102.084β = 90
c = 67.754γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data 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: 2013-06-19
    Type: Initial release
  • Version 1.1: 2013-08-07
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.3: 2023-12-06
    Changes: Data collection