Amidino-rocaglates: a potent class of eIF4A inhibitors
Files
Accepted manuscript
Date
2019-11-21
Authors
Chu, Jennifer
Zhang, Wenhan
Cencic, Regina
Devine, William G.
Beglov, Dmitri
Henkel, Thomas
Brown, Lauren E.
Vajda, Sandor
Porco, John A.
Pelletier, Jerry
Version
Accepted manuscript
OA Version
Citation
Jennifer Chu, Wenhan Zhang, Regina Cencic, William G Devine, Dmitri Beglov, Thomas Henkel, Lauren E Brown, Sandor Vajda, John A Porco, Jerry Pelletier. 2019. "Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors.." Cell Chem Biol, Volume 26, Issue 11, pp. 1586 - 1593.e3. https://doi.org/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.
Description
Published in final edited form as: Cell Chem Biol. 2019 November 21; 26(11): 1586–1593.e3. doi:10.1016/j.chembiol.2019.08.008.