3VHD

Hsp90 alpha N-terminal domain in complex with a macrocyclic inhibitor, CH5164840


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.52 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.0 of the entry. See complete history


Literature

Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors

Suda, A.Koyano, H.Hayase, T.Hada, K.Kawasaki, K.Komiyama, S.Hasegawa, K.Fukami, T.A.Sato, S.Miura, T.Ono, N.Yamazaki, T.Saitoh, R.Shimma, N.Shiratori, Y.Tsukuda, T.

(2012) Bioorg Med Chem Lett 22: 1136-1141

  • DOI: https://doi.org/10.1016/j.bmcl.2011.11.100
  • Primary Citation of Related Structures:  
    3VHA, 3VHC, 3VHD

  • PubMed Abstract: 

    Macrocyclic compounds bearing a 2-amino-6-arylpyrimidine moiety were identified as potent heat shock protein 90 (Hsp90) inhibitors by modification of 2-amino-6-aryltriazine derivative (CH5015765). We employed a macrocyclic structure as a skeleton of new inhibitors to mimic the geldanamycin-Hsp90 interactions. Among the identified inhibitors, CH5164840 showed high binding affinity for N-terminal Hsp90α (K(d)=0.52nM) and strong anti-proliferative activity against human cancer cell lines (HCT116 IC(50)=0.15μM, NCI-N87 IC(50)=0.066μM). CH5164840 displayed high oral bioavailability in mice (F=70.8%) and potent antitumor efficacy in a HCT116 human colorectal cancer xenograft model (tumor growth inhibition=83%).


  • Organizational Affiliation

    Kamakura Laboratories, Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan. sudaats@chugai-pharm.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha
A, B
229Homo sapiensMutation(s): 0 
Gene Names: HSP90AA1
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
VHE
Query on VHE

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-amino-18,20-dimethyl-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.1(2,6)]docosa-1(20),2,4,6(22),17(21),18-hexaene-10,16-dione
C19 H23 N5 O2 S
OMFBVBRFVYLRQT-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
VHE Binding MOAD:  3VHD Kd: 0.52 (nM) from 1 assay(s)
BindingDB:  3VHD Kd: 0.52 (nM) from 1 assay(s)
PDBBind:  3VHD Kd: 0.52 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.52 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.995α = 114.6
b = 53.061β = 91.12
c = 54.178γ = 90.17
Software Package:
Software NamePurpose
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-07-18
    Type: Initial release