2. Academic Validation
  3. Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action

Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action

  • J Med Chem. 2021 Nov 11;64(21):15727-15746. doi: 10.1021/acs.jmedchem.1c01014.
Christopher J Zerio 1,  Tyler A Cunningham 2,  Allison S Tulino 1,  Erin A Alimusa 1,  Thomas M Buckley 1,  Kohlson T Moore 1,  Matthew Dodson 1,  Nathan C Wilson 1,  Andrew J Ambrose 1,  Taoda Shi 1,  Jared Sivinski 1,  Derek J Essegian 2,  Donna D Zhang 1,  Stephan C Schürer 2 3,  Jonathan H Schatz 4 3,  Eli Chapman 1
Affiliations

Affiliations

  • 1 College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
  • 2 Miller School of Medicine, Department of Molecular and Cellular Pharmacology, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States.
  • 3 Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Avenue, Miami, Florida 33136, United States.
  • 4 Miller School of Medicine, Department of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States.
PMID: 34676755 DOI: 10.1021/acs.jmedchem.1c01014
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.

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