6WOK

Crystal structure of estrogen receptor alpha in complex with receptor degrader 6


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.31 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.

Liang, J.Blake, R.Chang, J.Friedman, L.S.Goodacre, S.Hartman, S.Ingalla, E.R.Kiefer, J.R.Kleinheinz, T.Labadie, S.Li, J.Lai, K.W.Liao, J.Mody, V.McLean, N.Metcalfe, C.Nannini, M.Otwine, D.Ran, Y.Ray, N.Roussel, F.Sambrone, A.Sampath, D.Vinogradova, M.Wai, J.Wang, T.Yeap, K.Young, A.Zbieg, J.Zhang, B.Zheng, X.Zhong, Y.Wang, X.

(2020) ACS Med Chem Lett 11: 1342-1347

  • DOI: https://doi.org/10.1021/acsmedchemlett.0c00224
  • Primary Citation of Related Structures:  
    6WOK

  • PubMed Abstract: 

    Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.


  • Organizational Affiliation

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Estrogen receptorA [auth D],
B [auth A],
C,
D [auth B]
280Homo sapiensMutation(s): 2 
Gene Names: ESR1ESRNR3A1
UniProt & NIH Common Fund Data Resources
Find proteins for P03372 (Homo sapiens)
Explore P03372 
Go to UniProtKB:  P03372
PHAROS:  P03372
GTEx:  ENSG00000091831 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03372
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
U6D (Subject of Investigation/LOI)
Query on U6D

Download Ideal Coordinates CCD File 
F [auth A],
H [auth C],
J [auth B]
(1R,3R)-1-(2,6-difluoro-4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline
C28 H33 F4 N3 O
YENNSFZGAPUOQB-XGCWNURASA-N
G9J
Query on G9J

Download Ideal Coordinates CCD File 
E [auth D],
G [auth A],
I [auth C]
(2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol
C22 H17 I O3
RWKXMXMLZHFKIZ-QFIPXVFZSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.31 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.172 
  • R-Value Observed: 0.175 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.609α = 86.61
b = 59.102β = 74.78
c = 94.718γ = 63.29
Software Package:
Software NamePurpose
PHENIXrefinement
SCALEPACKdata scaling
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: 2020-07-01
    Type: Initial release
  • Version 1.1: 2023-11-01
    Changes: Data collection, Database references, Structure summary