Rocaglates induce gain-of-function alterations to eIF4A and eIF4F
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Published version
Date
2020-02-25
Authors
Chu, Jennifer
Zhang, Wenhan
Cencic, Regina
O'Connor, Patrick B. F.
Robert, Francis
Devine, William G.
Selznick, Asher
Henkel, Thomas
Merrick, William C.
Brown, Lauren E.
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Published version
OA Version
Citation
Jennifer Chu, Wenhan Zhang, Regina Cencic, Patrick BF O'Connor, Francis Robert, William G Devine, Asher Selznick, Thomas Henkel, William C Merrick, Lauren E Brown, Pavel V Baranov, John A Porco, Jerry Pelletier. 2020. "Rocaglates induce gain-of-function alterations to eIF4A and eIF4F." Cell Rep, Volume 30, Issue 8, pp. 2481 - 2488.e5. https://doi.org/10.1016/j.celrep.2020.02.002
Abstract
Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.
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© 2020 The Author(s). This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.