Discovery of an eIF4A Inhibitor with a Novel Mechanism of Action.

Autor:	Zerio CJ; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Cunningham TA; Miller School of Medicine, Department of Molecular and Cellular Pharmacology, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States., Tulino AS; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Alimusa EA; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Buckley TM; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Moore KT; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Dodson M; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Wilson NC; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Ambrose AJ; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Shi T; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Sivinski J; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Essegian DJ; Miller School of Medicine, Department of Molecular and Cellular Pharmacology, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States., Zhang DD; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States., Schürer SC; Miller School of Medicine, Department of Molecular and Cellular Pharmacology, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States.; Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Avenue, Miami, Florida 33136, United States., Schatz JH; Miller School of Medicine, Department of Medicine, University of Miami, 1600 NW 10th Avenue, Miami, Florida 33136, United States.; Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Avenue, Miami, Florida 33136, United States., Chapman E; College of Pharmacy, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel Street, P.O. Box 210207, Tucson, Arizona 85721, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Nov 11; Vol. 64 (21), pp. 15727-15746. Date of Electronic Publication: 2021 Oct 22.
DOI:	10.1021/acs.jmedchem.1c01014
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu