Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action

Increased protein synthesis is a
requirement for malignant growth,
and as a result, translation has become a pharmaceutical target for
cancer. The initiation of cap-dependent translation is enzymatically
driven by the eukaryotic initiation factor (eIF)­4A, an ATP-powered
DEAD-box RNA-helicase that unwinds the messenger RNA secondary structure
upstream of the start codon, enabling translation of downstream genes.
A screen for inhibitors of eIF4A ATPase activity produced an intriguing
hit that, surprisingly, was not ATP-competitive. A medicinal chemistry
campaign produced the novel eIF4A inhibitor 28, which
decreased BJAB Burkitt lymphoma cell viability. Biochemical and cellular
studies, molecular docking, and functional assays uncovered that 28 is an RNA-competitive, ATP-uncompetitive inhibitor that
engages a novel pocket in the RNA groove of eIF4A and inhibits unwinding
activity by interfering with proper RNA binding and suppressing ATP
hydrolysis. Inhibition of eIF4A through this unique mechanism may
offer new strategies for targeting this promising intersection point
of many oncogenic pathways.