Details

Autor(en) / Beteiligte

• Fischer, Patrick D.
• Papadopoulos, Evangelos
• Dempersmier, Jon M.
• Wang, Zi-Fu
• Nowak, Radosław P.
• Donovan, Katherine A.
• Kalabathula, Joann
• Gorgulla, Christoph
• Junghanns, Pierre P.M.
• Kabha, Eihab
• Dimitrakakis, Nikolaos
• Petrov, Ognyan I.
• Mitsiades, Constantine
• Ducho, Christian
• Gelev, Vladimir
• Fischer, Eric S.
• Wagner, Gerhard
• Arthanari, Haribabu

Titel

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

Ist Teil von

• European journal of medicinal chemistry, 2021-07, Vol.219, p.113435-113435, Article 113435

Ort / Verlag

France: Elsevier Masson SAS

Erscheinungsjahr

2021

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Design of an eIF4E inhibitor i4EG-BiP, that binds to an internal site.•High resolution crystal structure of eIF4E bound to the inhibitor i4EG-BiP.•Specific inhibition of cap-dependent translation by i4EG-BiP.•Design cell-permeable eIF4E-targeting PROTACs based on i4EG-BiP and 4EGI-1.•Synthesis and testing of eIF4E PROTACs in biophysical and cellular assays.