2VCJ

4,5 Diaryl Isoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.305 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.225 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.

Brough, P.A.Aherne, W.Barril, X.Borgognoni, J.Boxall, K.Cansfield, J.E.Cheung, K.M.Collins, I.Davies, N.G.Drysdale, M.J.Dymock, B.Eccles, S.A.Finch, H.Fink, A.Hayes, A.Howes, R.Hubbard, R.E.James, K.Jordan, A.M.Lockie, A.Martins, V.Massey, A.Matthews, T.P.McDonald, E.Northfield, C.J.Pearl, L.H.Prodromou, C.Ray, S.Raynaud, F.I.Roughley, S.D.Sharp, S.Y.Surgenor, A.Walmsley, D.L.Webb, P.Wood, M.Workman, P.Wright, L.

(2008) J Med Chem 51: 196-218

  • DOI: https://doi.org/10.1021/jm701018h
  • Primary Citation of Related Structures:  
    2VCI, 2VCJ

  • PubMed Abstract: 

    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.


  • Organizational Affiliation

    Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K. 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-ALPHA236Homo 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
2EQ
Query on 2EQ

Download Ideal Coordinates CCD File 
B [auth A]5-(5-chloro-2,4-dihydroxyphenyl)-N-ethyl-4-[4-(morpholin-4-ylmethyl)phenyl]isoxazole-3-carboxamide
C23 H24 Cl N3 O5
APGOABVITLQCKW-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2EQ BindingDB:  2VCJ IC50: min: 21, max: 1.00e+4 (nM) from 3 assay(s)
EC50: 83 (nM) from 1 assay(s)
Binding MOAD:  2VCJ IC50: 21 (nM) from 1 assay(s)
PDBBind:  2VCJ IC50: 21 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.305 
  • R-Value Work: 0.221 
  • R-Value Observed: 0.225 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.038α = 90
b = 89.289β = 90
c = 99.516γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
d*TREKdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2007-12-11
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-02-28
    Changes: Database references
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description