3DU8

Crystal structure of GSK-3 beta in complex with NMS-869553A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery.

Menichincheri, M.Bargiotti, A.Berthelsen, J.Bertrand, J.A.Bossi, R.Ciavolella, A.Cirla, A.Cristiani, C.Croci, V.D'Alessio, R.Fasolini, M.Fiorentini, F.Forte, B.Isacchi, A.Martina, K.Molinari, A.Montagnoli, A.Orsini, P.Orzi, F.Pesenti, E.Pezzetta, D.Pillan, A.Poggesi, I.Roletto, F.Scolaro, A.Tato, M.Tibolla, M.Valsasina, B.Varasi, M.Volpi, D.Santocanale, C.Vanotti, E.

(2009) J Med Chem 52: 293-307

  • DOI: https://doi.org/10.1021/jm800977q
  • Primary Citation of Related Structures:  
    3DU8

  • PubMed Abstract: 

    Cdc7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. Cdc7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 inhibitors for the treatment of cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against Cdc7 kinase. Furthermore, we also describe the discovery of 89S, [(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one], as a potent ATP mimetic inhibitor of Cdc7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.


  • Organizational Affiliation

    Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, Milano, Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glycogen synthase kinase-3 beta
A, B
422Homo sapiensMutation(s): 0 
Gene Names: GSK3B
EC: 2.7.11.26
UniProt & NIH Common Fund Data Resources
Find proteins for P49841 (Homo sapiens)
Explore P49841 
Go to UniProtKB:  P49841
PHAROS:  P49841
GTEx:  ENSG00000082701 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP49841
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
553
Query on 553

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(7S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoroethyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one
C13 H14 F N5 O
LCBAQTCTQXHTJG-ZETCQYMHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
553 Binding MOAD:  3DU8 IC50: 146 (nM) from 1 assay(s)
PDBBind:  3DU8 IC50: 146 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 82.599α = 90
b = 85.81β = 90
c = 178.043γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
MxCuBEdata collection

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-03-03 
  • Deposition Author(s): Bossi, R.T.

Revision History  (Full details and data files)

  • Version 1.0: 2009-03-03
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description