3R92

Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.

Zapf, C.W.Bloom, J.D.McBean, J.L.Dushin, R.G.Golas, J.M.Liu, H.Lucas, J.Boschelli, F.Vogan, E.Levin, J.I.

(2011) Bioorg Med Chem Lett 21: 3627-3631

  • DOI: https://doi.org/10.1016/j.bmcl.2011.04.102
  • Primary Citation of Related Structures:  
    3R92

  • PubMed Abstract: 

    A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.


  • Organizational Affiliation

    Medicinal Chemistry, Pfizer, Pearl River, NY 10965, United States. christoph.zapf@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha226Homo sapiensMutation(s): 0 
Gene Names: HSP90AHSP90AA1HSPC1HSPCA
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
06J
Query on 06J

Download Ideal Coordinates CCD File 
B [auth A](3aR)-13,13,16-trimethyl-15-oxo-1,2,3,3a,4,5,12,14,15,17,18,19-dodecahydro-13H-10,6-(metheno)pyrrolo[2',1':3,4][1,4,9]triazacyclotetradecino[9,8-a]indole-7-carboxamide
C26 H34 N4 O2
WQTXERXALASGRT-GOSISDBHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
06J BindingDB:  3R92 IC50: 96 (nM) from 1 assay(s)
Binding MOAD:  3R92 IC50: 883 (nM) from 1 assay(s)
PDBBind:  3R92 IC50: 96 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.194 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.35α = 90
b = 90.355β = 90
c = 98.594γ = 90
Software Package:
Software NamePurpose
StructureStudiodata collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-06-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2020-04-15
    Changes: Data collection, Database references
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations