A comparative study of small molecules targeting eIF4A.

Abstract

The PI3K/Akt/mTOR kinase pathway is extensively deregulated in human cancers. One critical node under regulation of this signaling axis is eukaryotic initiation factor (eIF) 4F, a complex involved in the control of translation initiation rates. eIF4F-dependent addictions arise during tumor initiation and maintenance due to increased eIF4F activity-generally in response to elevated PI3K/Akt/mTOR signaling flux. There is thus much interest in exploring eIF4F as a small molecule target for the development of new anticancer drugs. The DEAD-box RNA helicase, eIF4A, is an essential subunit of eIF4F, and several potent small molecules (rocaglates, hippuristanol, pateamine A) affecting its activity have been identified and shown to demonstrate anticancer activity in vitro and in vivo in preclinical models. Recently, a number of new small molecules have been reported as having the capacity to target and inhibit eIF4A. Here, we undertook a comparative analysis of their biological activity and specificity relative to the eIF4A inhibitor, hippuristanol.

• Authors: Sai Kiran Naineni, Rayelle Itoua Maïga, Regina Cencic, Andrea A Putnam, Luis A Amador, Abimael D Rodriguez, Eckhard Jankowsky, Jerry Pelletier
• Journal: RNA (New York, N.Y.) (RNA) Vol. 26 Issue 5 Pg. 541-549 (05 2020) ISSN: 1469-9001 [Electronic] United States
• PMID: 32014999 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Naineni et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Chemical References

• Antineoplastic Agents
• Benzofurans
• Epoxy Compounds
• Eukaryotic Initiation Factor-4F
• Macrolides
• Small Molecule Libraries
• Sterols
• Thiazoles
• hippuristanol
• pateamine A
• rocagloic acid
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Eukaryotic Initiation Factor-4A

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Benzofurans (chemistry)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Epoxy Compounds (chemistry)
• Eukaryotic Initiation Factor-4A (antagonists & inhibitors, chemistry)
• Eukaryotic Initiation Factor-4F (antagonists & inhibitors, chemistry)
• Humans
• Macrolides (chemistry)
• Neoplasms (drug therapy, genetics)
• Phosphatidylinositol 3-Kinases (genetics)
• Protein Biosynthesis (drug effects)
• Proto-Oncogene Proteins c-akt (genetics)
• Small Molecule Libraries (chemistry, pharmacology)
• Sterols (chemistry, pharmacology)
• TOR Serine-Threonine Kinases (genetics)
• Thiazoles (chemistry)