7MEU

A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.166 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders.

Fischer, P.D.Papadopoulos, E.Dempersmier, J.M.Wang, Z.F.Nowak, R.P.Donovan, K.A.Kalabathula, J.Gorgulla, C.Junghanns, P.P.M.Kabha, E.Dimitrakakis, N.Petrov, O.I.Mitsiades, C.Ducho, C.Gelev, V.Fischer, E.S.Wagner, G.Arthanari, H.

(2021) Eur J Med Chem 219: 113435-113435

  • DOI: https://doi.org/10.1016/j.ejmech.2021.113435
  • Primary Citation of Related Structures:  
    7MEU

  • PubMed Abstract: 

    The eukaryotic translation initiation factor 4E (eIF4E) is the master regulator of cap-dependent protein synthesis. Overexpression of eIF4E is implicated in diseases such as cancer, where dysregulation of oncogenic protein translation is frequently observed. eIF4E has been an attractive target for cancer treatment. Here we report a high-resolution X-ray crystal structure of eIF4E in complex with a novel inhibitor (i4EG-BiP) that targets an internal binding site, in contrast to the previously described inhibitor, 4EGI-1, which binds to the surface. We demonstrate that i4EG-BiP is able to displace the scaffold protein eIF4G and inhibit the proliferation of cancer cells. We provide insights into how i4EG-BiP is able to inhibit cap-dependent translation by increasing the eIF4E-4E-BP1 interaction while diminishing the interaction of eIF4E with eIF4G. Leveraging structural details, we designed proteolysis targeted chimeras (PROTACs) derived from 4EGI-1 and i4EG-BiP and characterized these on biochemical and cellular levels. We were able to design PROTACs capable of binding eIF4E and successfully engaging Cereblon, which targets proteins for proteolysis. However, these initial PROTACs did not successfully stimulate degradation of eIF4E, possibly due to competitive effects from 4E-BP1 binding. Our results highlight challenges of targeted proteasomal degradation of eIF4E that must be addressed by future efforts.


  • Organizational Affiliation

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA; Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, 66123, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Eukaryotic translation initiation factor 4E
A, B
192Homo sapiensMutation(s): 0 
Gene Names: EIF4EEIF4EL1EIF4F
UniProt & NIH Common Fund Data Resources
Find proteins for P06730 (Homo sapiens)
Explore P06730 
Go to UniProtKB:  P06730
PHAROS:  P06730
GTEx:  ENSG00000151247 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06730
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
MGP
Query on MGP

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
7-METHYL-GUANOSINE-5'-TRIPHOSPHATE
C11 H19 N5 O14 P3
DKVRNHPCAOHRSI-KQYNXXCUSA-O
Z5D (Subject of Investigation/LOI)
Query on Z5D

Download Ideal Coordinates CCD File 
D [auth A](2E)-2-{2-[4-([1,1'-biphenyl]-4-yl)-1,3-thiazol-2-yl]hydrazinylidene}-3-(2-nitrophenyl)propanoic acid
C24 H18 N4 O4 S
JKEOZOHBIPDTTJ-LHLOQNFPSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MGP BindingDB:  7MEU Ki: 28 (nM) from 1 assay(s)
Kd: 10 (nM) from 1 assay(s)
IC50: min: 2360, max: 5720 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.91 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.161 
  • R-Value Observed: 0.166 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 38.812α = 90
b = 73.364β = 101.36
c = 61.866γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
XDSdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Cancer Institute (NIH/NCI)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2021-04-28
    Type: Initial release
  • Version 1.1: 2021-05-05
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Database references, Refinement description