A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders.
Binding Sites
Biphenyl Compounds
/ chemistry
Cell Line, Tumor
Cell Survival
/ drug effects
Drug Design
Eukaryotic Initiation Factor-4E
/ antagonists & inhibitors
Humans
Kinetics
Molecular Docking Simulation
Prodrugs
/ chemical synthesis
Protein Interaction Maps
/ drug effects
Proteolysis
/ drug effects
Proteomics
Recombinant Proteins
/ biosynthesis
Prodrug
Protein-protein interaction inhibitor
Translation inhibitor
eIF4E PROTAC
eIF4E inhibitor
eIF4E-eIF4G inhibitor
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
05 Jul 2021
05 Jul 2021
Historique:
received:
11
11
2020
revised:
23
03
2021
accepted:
01
04
2021
pubmed:
24
4
2021
medline:
12
8
2021
entrez:
23
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33892272
pii: S0223-5234(21)00284-1
doi: 10.1016/j.ejmech.2021.113435
pmc: PMC8846605
mid: NIHMS1696715
pii:
doi:
Substances chimiques
Biphenyl Compounds
0
Eukaryotic Initiation Factor-4E
0
Prodrugs
0
Recombinant Proteins
0
diphenyl
2L9GJK6MGN
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
113435Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM132079
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA200913
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM136859
Pays : United States
Organisme : NIH HHS
ID : S10 OD028526
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Masson SAS. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: E. S. F. is a founder, science advisory board member and equity holder in Civetta, Jengu (board member) and Neomorph, an equity holder in C4, and a consultant to Astellas, Novartis, Deerfield, RA Capital and EcoR1. The Fischer lab receives or has received research funding from Novartis, Astellas, Ajax and Deerfield. G.W. is co-founder of PIC Therapeutics, Cellmig biolabs, Skinap therapeutics and Virtual Discovery. H.A. is an equity holder in PIC Therapeutics. The research described here is scientifically and financially independent of the efforts in any of the above-mentioned companies.
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