5GGZ

Crystal structure of novel inhibitor bound with Hsp90


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

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Literature

Novel Tetrahydropyrido[4,3-d]pyrimidines as Potent Inhibitors of Chaperone Heat Shock Protein 90

Jiang, F.Wang, H.J.Jin, Y.H.Zhang, Q.Wang, Z.H.Jia, J.M.Liu, F.Wang, L.Bao, Q.C.Li, D.D.You, Q.D.Xu, X.L.

(2016) J Med Chem 59: 10498-10519

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b00912
  • Primary Citation of Related Structures:  
    5GGZ

  • PubMed Abstract: 

    Heat shock protein 90 (Hsp90) is a potential target for oncology therapeutics. Some inhibitors have shown antitumor effects in clinical trials, spurring the discovery of small molecule Hsp90 inhibitors. Here, we describe the structural optimization studies of a hit compound, tetrahydropyrido[4,3-d]pyrimidine-based Hsp90 inhibitor 15, which exhibits inhibitory activity against Hsp90. A series of analogues were synthesized, and their structure-activity and structure-property relationships were analyzed. These explorations led to the discovery of compound 73, which exhibited potent in vitro activities, good physicochemical properties, favorable ADME properties, and a potent antitumor effect in an HCT116 xenograft model. Furthermore, 73 exhibited no ocular toxicity in a rat retinal damage model, suggesting it is a relatively safe Hsp90 inhibitor. As a promising antitumor agent, 73 was progressed for further preclinical evaluation.


  • Organizational Affiliation

    State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization and ‡Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University , Nanjing 210009, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alphaA [auth B],
B [auth A],
C [auth D],
D [auth C]
210Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
6TN Binding MOAD:  5GGZ IC50: 56 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.841α = 90
b = 88.581β = 90.08
c = 99.382γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-03-08
    Type: Initial release
  • Version 1.1: 2024-03-20
    Changes: Data collection, Database references