2. Academic Validation
  3. Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors

Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors

  • Cell Chem Biol. 2019 Nov 21;26(11):1586-1593.e3. doi: 10.1016/j.chembiol.2019.08.008.
Jennifer Chu 1,  Wenhan Zhang 2,  Regina Cencic 1,  William G Devine 2,  Dmitri Beglov 3,  Thomas Henkel 4,  Lauren E Brown 2,  Sandor Vajda 5,  John A Porco Jr 6,  Jerry Pelletier 7
Affiliations

Affiliations

  • 1 Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
  • 2 Department of Chemistry, 590 Commonwealth Avenue, Boston University, Boston, MA 02215, USA; Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA.
  • 3 Department of Biomedical Engineering, Boston University, Boston, MA, USA.
  • 4 IMAX Discovery GmbH, Dortmund, Germany.
  • 5 Department of Chemistry, 590 Commonwealth Avenue, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA, USA.
  • 6 Department of Chemistry, 590 Commonwealth Avenue, Boston University, Boston, MA 02215, USA; Center for Molecular Discovery (BU-CMD), Boston University, Boston, MA, USA. Electronic address: porco@bu.edu.
  • 7 Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Oncology, McGill University, Montreal, Canada; Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, Canada. Electronic address: jerry.pelletier@mcgill.ca.
PMID: 31519508 DOI: 10.1016/j.chembiol.2019.08.008
Abstract

Rocaglates share a common cyclopenta[b]benzofuran core that inhibits eukaryotic translation initiation by modifying the behavior of the RNA helicase, eIF4A. Working as interfacial inhibitors, rocaglates stabilize the association between eIF4A and RNA, which can lead to the formation of steric barriers that block initiating ribosomes. There is significant interest in the development and expansion of rocaglate derivatives, as several members of this family have been shown to possess potent anti-neoplastic activity in vitro and in vivo. To further our understanding of rocaglate diversity and drug design, herein we explore the RNA clamping activity of >200 unique rocaglate derivatives. Through this, we report on the identification and characterization of a potent class of synthetic rocaglates called amidino-rocaglates. These compounds are among the most potent rocaglates documented to date and, taken together, this work offers important information that will guide the future design of rocaglates with improved biological properties.

Keywords

amidino-rocaglates; eIF4A; eIF4F; interfacial inhibitor; translation initiation.

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