4HYF

Structural basis and SAR for OD 270, a lead stage 1,2,4-triazole based specific Tankyrase1/2 inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Structural Basis and SAR for G007-LK, a Lead Stage 1,2,4-Triazole Based Specific Tankyrase 1/2 Inhibitor.

Voronkov, A.Holsworth, D.D.Waaler, J.Wilson, S.R.Ekblad, B.Perdreau-Dahl, H.Dinh, H.Drewes, G.Hopf, C.Morth, J.P.Krauss, S.

(2013) J Med Chem 56: 3012-3023

  • DOI: https://doi.org/10.1021/jm4000566
  • Primary Citation of Related Structures:  
    4HYF

  • PubMed Abstract: 

    Tankyrases 1 and 2 (TNKS1/2) are promising pharmacological biotargets with possible applications for the development of novel anticancer therapeutics. A focused structure-activity relationship study was conducted based on the tankyrase inhibitor JW74 (1). Chemical analoging of 1 improved the 1,2,4-triazole based core and led to 4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile (G007-LK), a potent, "rule of 5" compliant and a metabolically stable TNKS1/2 inhibitor. G007-LK (66) displayed high selectivity toward tankyrases 1 and 2 with biochemical IC50 values of 46 nM and 25 nM, respectively, and a cellular IC50 value of 50 nM combined with an excellent pharmacokinetic profile in mice. The PARP domain of TNKS2 was cocrystallized with 66, and the X-ray structure was determined at 2.8 Å resolution in the space group P3221. The structure revealed that 66 binds to unique structural features in the extended adenosine binding pocket which forms the structural basis for the compound's high target selectivity and specificity. Our study provides a significantly optimized compound for targeting TNKS1/2 in vitro and in vivo.


  • Organizational Affiliation

    SFI CAST Biomedical Innovation Center, Unit for Cell Signaling, Oslo University Hospital, Forskningsparken, Gaustadalleén 21, 0349 Oslo, Norway.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tankyrase-2
A, B, C
240Homo sapiensMutation(s): 0 
Gene Names: PARP5BTANK2TNKLTNKS2
EC: 2.4.2.30
UniProt & NIH Common Fund Data Resources
Find proteins for Q9H2K2 (Homo sapiens)
Explore Q9H2K2 
Go to UniProtKB:  Q9H2K2
PHAROS:  Q9H2K2
GTEx:  ENSG00000107854 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9H2K2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1AK
Query on 1AK

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C]
4-{5-[(E)-2-{4-(2-chlorophenyl)-5-[5-(methylsulfonyl)pyridin-2-yl]-4H-1,2,4-triazol-3-yl}ethenyl]-1,3,4-oxadiazol-2-yl}benzonitrile
C25 H16 Cl N7 O3 S
HIWVLHPKZNBSBE-OUKQBFOZSA-N
NCA
Query on NCA

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B],
J [auth C]
NICOTINAMIDE
C6 H6 N2 O
DFPAKSUCGFBDDF-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1AK PDBBind:  4HYF IC50: 25 (nM) from 1 assay(s)
BindingDB:  4HYF IC50: min: 25, max: 86 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 151.54α = 90
b = 151.54β = 90
c = 140.52γ = 120
Software Package:
Software NamePurpose
RemDAqdata collection
PHASERphasing
PHENIXrefinement
PROCESSdata reduction
SCALAdata 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: 2013-03-20
    Type: Initial release
  • Version 1.1: 2013-05-01
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description