2XJX

Structure of HSP90 with small molecule inhibitor bound


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.66 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.158 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of (2,4-Dihydroxy-5-Isopropylphenyl)-[5-(4-Methylpiperazin-1-Ylmethyl)-1,3-Dihydroisoindol-2-Yl]Methanone (at13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design.

Woodhead, A.J.Angove, H.Carr, M.G.Chessari, G.Congreve, M.Coyle, J.E.Cosme, J.Graham, B.Day, P.J.Downham, R.Fazal, L.Feltell, R.Figueroa, E.Frederickson, M.Lewis, J.Mcmenamin, R.Murray, C.W.O'Brien, M.A.Parra, L.Patel, S.Phillips, T.Rees, D.C.Rich, S.Smith, D.M.Trewartha, G.Vinkovic, M.Williams, B.Woolford, A.J.

(2010) J Med Chem 53: 5956

  • DOI: https://doi.org/10.1021/jm100060b
  • Primary Citation of Related Structures:  
    2XAB, 2XJG, 2XJJ, 2XJX

  • PubMed Abstract: 

    Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.


  • Organizational Affiliation

    Medicinal Chemistry, Astex Therapeutics, Ltd., Cambridge, UK. a.woodhead@astex-therapeutics.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HEAT SHOCK PROTEIN HSP 90-ALPHA249Homo 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
XJX
Query on XJX

Download Ideal Coordinates CCD File 
B [auth A]Onalespib
C24 H31 N3 O3
IFRGXKKQHBVPCQ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
XJX PDBBind:  2XJX Kd: 0.71 (nM) from 1 assay(s)
Binding MOAD:  2XJX Kd: 0.71 (nM) from 1 assay(s)
BindingDB:  2XJX IC50: min: 13, max: 350 (nM) from 7 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.66 Å
  • R-Value Free: 0.208 
  • R-Value Work: 0.155 
  • R-Value Observed: 0.158 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.95α = 90
b = 41.05β = 101.86
c = 49.23γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-11
    Type: Initial release
  • Version 1.1: 2013-04-24
    Changes: Other, Structure summary, Version format compliance
  • Version 1.2: 2015-02-18
    Changes: Non-polymer description, Structure summary