Discovery of Novel 1,4-Diacylpiperazines as Selective and Cell-Active eIF4A3 Inhibitors

Eukaryotic
initiation factor 4A3 (eIF4A3), a member of the DEAD-box
RNA helicase family, is one of the core components of the exon junction
complex (EJC). The EJC is known to be involved in a variety of RNA
metabolic processes typified by nonsense-mediated RNA decay (NMD).
In order to identify molecular probes to investigate the functions
and therapeutic relevance of eIF4A3, a search for selective eIF4A3
inhibitors was conducted. Through the chemical optimization of 1,4-diacylpiperazine
derivatives identified via high-throughput screening (HTS), we discovered
the first reported selective eIF4A3 inhibitor 53a exhibiting
cellular NMD inhibitory activity. A surface plasmon resonance (SPR)
biosensing assay ascertained the direct binding of 53a and its analog 52a to eIF4A3 and revealed that the
binding occurs at a non-ATP binding site. Compounds 52a and 53a represent novel molecular probes for further
study of eIF4A3, the EJC, and NMD.