3R91

Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.

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

(2011) Bioorg Med Chem Lett 21: 3411-3416

  • DOI: https://doi.org/10.1016/j.bmcl.2011.03.112
  • Primary Citation of Related Structures:  
    3R91

  • PubMed Abstract: 

    A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.


  • Organizational Affiliation

    Medicinal Chemistry, Pfizer, 401 N Middletown Road, Pearl River, NY 10965, United States. chzapf@gmail.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
06H
Query on 06H

Download Ideal Coordinates CCD File 
B [auth A](6S)-4,6,15,15,18-pentamethyl-5,17-dioxo-2,3,4,5,6,7,14,15,16,17-decahydro-1H-12,8-(metheno)[1,4,9]triazacyclotetradecino[9,8-a]indole-9-carboxamide
C25 H32 N4 O3
QPCQIBFESZKAHD-HNNXBMFYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
06H PDBBind:  3R91 IC50: 92 (nM) from 1 assay(s)
Binding MOAD:  3R91 IC50: 92 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.186 
  • R-Value Observed: 0.187 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 67.042α = 90
b = 90.25β = 90
c = 97.797γ = 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: 2011-05-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description