3K98

HSP90 N-terminal domain in complex with (1R)-2-(5-chloro-2,4-dihydroxybenzoyl)-N-ethylisoindoline-1-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone.

Kung, P.P.Huang, B.Zhang, G.Zhou, J.Z.Wang, J.Digits, J.A.Skaptason, J.Yamazaki, S.Neul, D.Zientek, M.Elleraas, J.Mehta, P.Yin, M.J.Hickey, M.J.Gajiwala, K.S.Rodgers, C.Davies, J.F.Gehring, M.R.

(2010) J Med Chem 53: 499-503

  • DOI: https://doi.org/10.1021/jm901209q
  • Primary Citation of Related Structures:  
    3K97, 3K98, 3K99

  • PubMed Abstract: 

    The discovery and optimization of potency and metabolic stability of a novel class of dihyroxyphenylisoindoline amides as Hsp90 inhibitors are presented. Optimization of a screening hit using structure-based design and modification of log D and chemical structural features led to the identification of a class of orally bioavailable non-quinone-containing Hsp90 inhibitors. This class is exemplified by 14 and 15, which possess improved cell potency and pharmacokinetic profiles compared with the original screening hit.


  • Organizational Affiliation

    Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA. peipei.kung@pfizer.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha
A, B
232Homo sapiensMutation(s): 0 
Gene Names: HSP90AA1HSP90AHSPC1HSPCA
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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1RC
Query on 1RC

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
(1R)-2-[(5-chloro-2,4-dihydroxyphenyl)carbonyl]-N-ethyl-2,3-dihydro-1H-isoindole-1-carboxamide
C18 H17 Cl N2 O4
QITRQXXSCAOQLZ-MRXNPFEDSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
D [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
1RC Binding MOAD:  3K98 Ki: 1 (nM) from 1 assay(s)
PDBBind:  3K98 Kd: 1 (nM) from 1 assay(s)
BindingDB:  3K98 IC50: 300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.986α = 90
b = 80.052β = 90
c = 118.091γ = 90
Software Package:
Software NamePurpose
MAR345data collection
CNXrefinement
HKL-2000data reduction
SCALEPACKdata scaling
CNXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-02-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations