3HEK

HSP90 N-terminal domain in complex with 1-{4-[(2R)-1-(5-chloro-2,4-dihydroxybenzoyl)pyrrolidin-2-yl]benzyl}-3,3-difluoropyrrolidinium


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.0 of the entry. See complete history


Literature

Solution-phase parallel synthesis of Hsp90 inhibitors

Cho-Schultz, S.Patten, M.J.Huang, B.Elleraas, J.Gajiwala, K.S.Hickey, M.J.Wang, J.Mehta, P.P.Kang, P.Gehring, M.R.Kung, P.P.Sutton, S.C.

(null) J Comb Chem 11: 860-874

  • DOI: https://doi.org/10.1021/cc900056d
  • Primary Citation of Related Structures:  
    3HEK

  • PubMed Abstract: 

    As part of an oncology chemistry program directed toward discovery of orally bioavailable inhibitors of the 90 kDa heat shock protein (Hsp90), several solution-phase libraries were designed and prepared. A 2 x 89 library of racemic resorcinol amides was prepared affording 131 purified compounds. After evaluation in a binding assay, followed by an AKT-Luminex cellular assay, three potent analogs had functional activity between 0.1 and 0.3 microM. Resolution by preparative chiral SFC chromatography led to (+)-15, (+)-16, and (+)-17 having functional IC(50) = 27, 43, and 190 nM, respectively. (+)-15 exhibited high clearance in human hepatocytes driven primarily by glucuronidation as confirmed by metabolite identification. A second 8 x 14 exploratory library was designed to investigate heterocyclic replacements of the resorcinol ring. The second library highlights the use of the (-)-sparteine-mediated enantioselective Pd-catalyzed alpha-arylation of N-Boc-pyrrolidine to prepare chiral 2-arylpyrrolidines in parallel.


  • Organizational Affiliation

    Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, California 92121, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Heat shock protein HSP 90-alpha
A, B
226Homo sapiensMutation(s): 0 
Gene Names: HSP90HSP90AHSP90AA1HSPC1HSPCA
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
BD0
Query on BD0

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
[(2~{R})-2-[4-[[3,3-bis(fluoranyl)pyrrolidin-1-yl]methyl]phenyl]pyrrolidin-1-yl]-[5-chloranyl-2,4-bis(oxidanyl)phenyl]methanone
C22 H23 Cl F2 N2 O3
MKPBMJPMGDZEOP-GOSISDBHSA-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
BD0 Binding MOAD:  3HEK Ki: 5.4 (nM) from 1 assay(s)
PDBBind:  3HEK Ki: 5.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.083α = 90
b = 80.16β = 90
c = 117.434γ = 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: 2009-09-29
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 2.0: 2023-05-17
    Changes: Database references, Derived calculations, Non-polymer description, Structure summary