Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F

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 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 influence their biological activities. Through this, we find that most rocaglates preferentially repress translation of mRNAs containing purine rich 5’ leaders but intriguingly, certain rocaglates lack this bias in translation repression. We also uncover a novel aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to sequestration of the complex onto RNA. Anti-FLAG eCLIP-seq with Input, vehicle (DMSO), Silvestrol, CR-1-31-B treatment in FLAG-tagged eIF4A strain