Rocaglates Induce Gain-of-Function Alterations to eIF4A and eIF4F
Jennifer Chu,
Wenhan Zhang,
Regina Cencic,
Patrick B.F. O’Connor,
Francis Robert,
William G. Devine,
Asher Selznick,
Thomas Henkel,
William C. Merrick,
Lauren E. Brown,
Pavel V. Baranov,
John A. Porco, Jr.,
Jerry Pelletier
Affiliations
Jennifer Chu
Department of Biochemistry, McGill University, Montreal, QC, Canada
Wenhan Zhang
Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA
Regina Cencic
Department of Biochemistry, McGill University, Montreal, QC, Canada
Patrick B.F. O’Connor
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
Francis Robert
Department of Biochemistry, McGill University, Montreal, QC, Canada
William G. Devine
Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA
Asher Selznick
Department of Biochemistry, McGill University, Montreal, QC, Canada
Thomas Henkel
IMAX Discovery GmbH, Dortmund, Germany
William C. Merrick
Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106-4935, USA
Lauren E. Brown
Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA
Pavel V. Baranov
School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, Russia
John A. Porco, Jr.
Department of Chemistry and Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA; Corresponding author
Jerry Pelletier
Department of Biochemistry, McGill University, Montreal, QC, Canada; Department of Oncology, McGill University, Montreal, QC, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada; Corresponding author
Summary: 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. : Rocaglates are a diverse family of small molecules that inhibit eIF4A. Chu et al. undertake a comparative analysis of the bioactivity of >200 rocaglates and uncover nuances in their mechanisms of action. Rocaglates interfere with eIF4F release from the cap and exert a bystander effect to inhibit translation. Keywords: rocaglates, eIF4A, eIF4F, translation initiation, interfacial inhibitor
