Justin T Ernst, Peggy A Thompson, Christian Nilewski, Paul A Sprengeler, Samuel Sperry, Garrick Packard, Theodore Michels, Alan Xiang, Chinh Tran, Christopher J Wegerski, Boreth Eam, Nathan P Young, Sarah Fish, Joan Chen, Haleigh Howard, Jocelyn Staunton, Jolene Molter, Jeff Clarine, Andres Nevarez, Gary G Chiang, Jim R Appleman, Kevin R Webster, Siegfried H Reich
Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products ( i.e. , rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity...
May 29, 2020: Journal of Medicinal Chemistry