2WI2

Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.237 
  • R-Value Observed: 0.239 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Combining Hit Identification Strategies: Fragment- Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-D]Pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.

Brough, P.A.Barril, X.Borgognoni, J.Chene, P.Davies, N.G.M.Davis, B.Drysdale, M.J.Dymock, B.Eccles, S.A.Garcia-Echeverria, C.Fromont, C.Hayes, A.Hubbard, R.E.Jordan, A.M.Jensen, M.R.Massey, A.Merrett, A.Padfield, A.Parsons, R.Radimerski, T.Raynaud, F.I.Robertson, A.Roughley, S.D.Schoepfer, J.Simmonite, H.Sharp, S.Y.Surgenor, A.Valenti, M.Walls, S.Webb, P.Wood, M.Workman, P.Wright, L.

(2009) J Med Chem 52: 4794

  • DOI: https://doi.org/10.1021/jm900357y
  • Primary Citation of Related Structures:  
    2WI1, 2WI2, 2WI3, 2WI4, 2WI5, 2WI6, 2WI7

  • PubMed Abstract: 

    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.


  • Organizational Affiliation

    Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, UK. p.brough@vernalis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEAT SHOCK PROTEIN HSP 90-ALPHA
A, B
236Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
ZZ3 Binding MOAD:  2WI2 IC50: 3.50e+5 (nM) from 1 assay(s)
PDBBind:  2WI2 IC50: 3.50e+5 (nM) from 1 assay(s)
BindingDB:  2WI2 IC50: 3.50e+5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.09 Å
  • R-Value Free: 0.289 
  • R-Value Work: 0.237 
  • R-Value Observed: 0.239 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 64.271α = 90
b = 88.442β = 90
c = 98.589γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
d*TREKdata reduction
d*TREKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2009-07-28
    Type: Initial release
  • Version 1.1: 2011-08-10
    Changes: Database references, Derived calculations, Non-polymer description, Other, Refinement description, Structure summary, Version format compliance
  • Version 1.2: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description