Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action

Christopher J. Zerio, Tyler A. Cunningham, Allison S. Tulino, Erin A. Alimusa, Thomas M. Buckley, Kohlson T. Moore, Matthew Dodson, Nathan C. Wilson, Andrew J. Ambrose, Taoda Shi, Jared Sivinski, Derek J. Essegian, Donna D. Zhang, Stephan C. Schürer, Jonathan H. Schatz, Eli Chapman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15727-15746
Number of pages20
JournalJournal of Medicinal Chemistry
Volume64
Issue number21
DOIs
StatePublished - Nov 11 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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