ArticleEuropean journal of medicinal chemistry2021
A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders.
Article in European journal of medicinal chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 32 citations in OpenAlex.
- Discovery of a small-molecule inhibitor of eIF4E suppressing tumor proliferation via lipid metabolic reprogramming.Journal of advanced research · 2026Article
- Proteolysis-targeting chimera (PROTAC) in cancer: design principles and applications on "undruggable" targets.Biomarker research · 2026Review
- Review
- Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.Communications chemistry · 2025Review
- Chemical Probes for Studying the Eukaryotic Translation Initiation Factor 4E (eIF4E)-Regulated Translatome in Cancer.ACS pharmacology & translational science · 2025Review
- Integrating fragment-based screening with targeted protein degradation and genetic rescue to explore eIF4E function.Nature communications · 2024Article
- miR-483-5p orchestrates the initiation of protein synthesis by facilitating the decrease in phosphorylated Ser209eIF4E and 4E-BP1 levels.Scientific reports · 2024Article
- Nano-Proteolysis Targeting Chimeras (Nano-PROTACs) in Cancer Therapy.International journal of nanomedicine · 2024Review
- Inhibition of Eukaryotic Initiating Factor eIF4E Overcomes Abemaciclib Resistance in Gastric Cancer.Current medical science · 2023Article
- Medicinal chemistry approaches to target the MNK-eIF4E axis in cancer.RSC medicinal chemistry · 2023Review
- Review
- Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation.Chemical Society reviews · 2022Review
- PROTACs: great opportunities for academia and industry (an update from 2020 to 2021).Signal transduction and targeted therapy · 2022Review
- AZD5438-PROTAC: A selective CDK2 degrader that protects against cisplatin- and noise-induced hearing loss.European journal of medicinal chemistry · 2021Article
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Authors and funding
18 authors at 4 institutions in 3 countries.
Funding
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.
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Registered trials
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