Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase

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. A focused effort was undertaken
utilizing a ligand-based design strategy to identify a chemotype with
optimized physicochemical properties. Also, detailed mechanistic studies
were undertaken to further elucidate mRNA sequence selectivity, key
regulated target genes, and the associated antitumor phenotype. This
work led to the design of eFT226 (Zotatifin), a compound
with excellent physicochemical properties and significant antitumor
activity that supports clinical development.