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

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

doi:10.1016/j.ejmech.2021.113435

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

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

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

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.

Original language	English
Article number	113435
Journal	European Journal of Medicinal Chemistry
Volume	219
DOIs	https://doi.org/10.1016/j.ejmech.2021.113435
State	Published - 5 Jul 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Masson SAS

Funding

PDF acknowledges the Chleck Foundation. HA acknowledges funding from the Claudia Adams Barr Program for Innovative Cancer Research and from NIH (GM136859). G.W. acknowledges support from NIH grant GM132079 and CA200913. We thank Dr. Kendra Leigh for her critical comments on the manuscript. 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. PDF acknowledges the Chleck Foundation. HA acknowledges funding from the Claudia Adams Barr Program for Innovative Cancer Research and from NIH (GM136859). G.W. acknowledges support from NIH grant GM132079 and CA200913 . We thank Dr. Kendra Leigh for her critical comments on the manuscript.

Funders	Funder number
Chleck Foundation
National Institutes of Health	CA200913, GM136859, GM132079
Astellas Pharma US
Novartis

Keywords

Prodrug
Protein-protein interaction inhibitor
Translation inhibitor
eIF4E PROTAC
eIF4E inhibitor
eIF4E-eIF4G inhibitor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2021.113435

Cite this

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). A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders. European Journal of Medicinal Chemistry, 219, Article 113435. https://doi.org/10.1016/j.ejmech.2021.113435

@article{d13caedec525487992cdf76608247f17,

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

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.",

keywords = "Prodrug, Protein-protein interaction inhibitor, Translation inhibitor, eIF4E PROTAC, eIF4E inhibitor, eIF4E-eIF4G inhibitor",

author = "Fischer, \{Patrick D.\} and Evangelos Papadopoulos and Dempersmier, \{Jon M.\} and Wang, \{Zi Fu\} and Nowak, \{Rados{\l}aw P.\} and Donovan, \{Katherine A.\} and Joann Kalabathula and Christoph Gorgulla and Junghanns, \{Pierre P.M.\} and Eihab Kabha and Nikolaos Dimitrakakis and Petrov, \{Ognyan I.\} and Constantine Mitsiades and Christian Ducho and Vladimir Gelev and Fischer, \{Eric S.\} and Gerhard Wagner and Haribabu Arthanari",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Masson SAS",

year = "2021",

month = jul,

day = "5",

doi = "10.1016/j.ejmech.2021.113435",

language = "אנגלית",

volume = "219",

journal = "European Journal of Medicinal Chemistry",

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Fischer, PD, Papadopoulos, E, Dempersmier, JM, Wang, ZF, Nowak, RP, Donovan, KA, Kalabathula, J, Gorgulla, C, Junghanns, PPM, Kabha, E, Dimitrakakis, N, Petrov, OI, Mitsiades, C, Ducho, C, Gelev, V, Fischer, ES, Wagner, G & Arthanari, H 2021, 'A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders', European Journal of Medicinal Chemistry, vol. 219, 113435. https://doi.org/10.1016/j.ejmech.2021.113435

TY - JOUR

T1 - A biphenyl inhibitor of eIF4E targeting an internal binding site enables the design of cell-permeable PROTAC-degraders

AU - Fischer, Patrick D.

AU - Papadopoulos, Evangelos

AU - Dempersmier, Jon M.

AU - Wang, Zi Fu

AU - Nowak, Radosław P.

AU - Donovan, Katherine A.

AU - Kalabathula, Joann

AU - Gorgulla, Christoph

AU - Junghanns, Pierre P.M.

AU - Kabha, Eihab

AU - Dimitrakakis, Nikolaos

AU - Petrov, Ognyan I.

AU - Mitsiades, Constantine

AU - Ducho, Christian

AU - Gelev, Vladimir

AU - Fischer, Eric S.

AU - Wagner, Gerhard

AU - Arthanari, Haribabu

PY - 2021/7/5

Y1 - 2021/7/5

N2 - 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.

AB - 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.

KW - Prodrug

KW - Protein-protein interaction inhibitor

KW - Translation inhibitor

KW - eIF4E PROTAC

KW - eIF4E inhibitor

KW - eIF4E-eIF4G inhibitor

UR - https://www.scopus.com/pages/publications/85104481259

U2 - 10.1016/j.ejmech.2021.113435

DO - 10.1016/j.ejmech.2021.113435

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C2 - 33892272

AN - SCOPUS:85104481259

SN - 0223-5234

VL - 219

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 113435

ER -

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

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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