2YKB

Tricyclic series of Hsp90 inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-C]Pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.

Vallee, F.Carrez, C.Pilorge, F.Dupuy, A.Parent, A.Bertin, L.Thompson, F.Ferrari, P.Fassy, F.Lamberton, A.Thomas, A.Arrebola, R.Guerif, S.Rohaut, A.Certal, V.Ruxer, J.M.Delorme, C.Jouanen, A.Dumas, J.Grepin, C.Combeau, C.Goulaouic, H.Dereu, N.Mikol, V.Mailliet, P.Minoux, H.

(2011) J Med Chem 54: 7206

  • DOI: https://doi.org/10.1021/jm200784m
  • Primary Citation of Related Structures:  
    2YJW, 2YJX, 2YK2, 2YK9, 2YKB, 2YKC, 2YKE, 2YKI, 2YKJ

  • PubMed Abstract: 

    A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.


  • Organizational Affiliation

    Sanofi-Aventis Research and Development, 13 Quai Jules Guesde, BP 14, 94400 Vitry-sur-Seine, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEAT SHOCK PROTEIN HSP 90-ALPHA209Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P07900 (Homo sapiens)
Explore P07900 
Go to UniProtKB:  P07900
PHAROS:  P07900
GTEx:  ENSG00000080824 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP07900
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
YKB
Query on YKB

Download Ideal Coordinates CCD File 
B [auth A]N-[4-(3H-IMIDAZO[4,5-C]PYRIDIN-2-YL)-9H-FLUOREN-9-YL]-SUCCINAMIDE
C23 H19 N5 O2
ROTVJYWUPWSGIX-JOCHJYFZSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
YKB BindingDB:  2YKB IC50: 5.00e+4 (nM) from 1 assay(s)
PDBBind:  2YKB IC50: 1100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.93 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.202 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.348α = 90
b = 90.627β = 90
c = 98.638γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
PROCESSdata 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: 2011-10-19
    Type: Initial release
  • Version 1.1: 2011-11-02
    Changes: Database references