3RKZ

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor capable of significantly decreasing tumor volume in a mouse xenograft model.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.57 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model.

Zapf, C.W.Bloom, J.D.Li, Z.Dushin, R.G.Nittoli, T.Otteng, M.Nikitenko, A.Golas, J.M.Liu, H.Lucas, J.Boschelli, F.Vogan, E.Olland, A.Johnson, M.Levin, J.I.

(2011) Bioorg Med Chem Lett 21: 4602-4607

  • DOI: https://doi.org/10.1016/j.bmcl.2011.05.102
  • Primary Citation of Related Structures:  
    3RKZ

  • PubMed Abstract: 

    An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.


  • 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
06T
Query on 06T

Download Ideal Coordinates CCD File 
B [auth A](5R,6S)-3-(L-alanyl)-5,6,15,15,18-pentamethyl-17-oxo-2,3,4,5,6,7,14,15,16,17-decahydro-1H-12,8-(metheno)[1,5,9]triazacyclotetradecino[1,2-a]indole-9-carboxamide
C28 H39 N5 O3
JSSUIPOIXFFFQU-NJAFHUGGSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
06T Binding MOAD:  3RKZ IC50: 83 (nM) from 1 assay(s)
PDBBind:  3RKZ IC50: 83 (nM) from 1 assay(s)
BindingDB:  3RKZ IC50: 83 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.57 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.167 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.001α = 90
b = 90.178β = 90
c = 97.957γ = 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 

Revision History  (Full details and data files)

  • Version 1.0: 2011-07-13
    Type: Initial release
  • Version 1.1: 2011-08-03
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description