Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors

Chu, Jennifer; Zhang, Wenhan; Cencic, Regina; Devine, William G.; Beglov, Dmitri; Henkel, Thomas; Brown, Lauren E.; Vajda, Sándor; Porco, John A.; Pelletier, Jerry

doi:10.1016/j.chembiol.2019.08.008

Cited by 52 publications

(73 citation statements)

References 30 publications

(37 reference statements)

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“…While the unwinding rate depends on the thermodynamic stability of the duplex substrate and not its length nor sequence, ssRNA tails on either end increase the rate by ~30% [ 46 ]. Furthermore, eIF4A1 and eIF4A2 have slight, inherent biases for binding polypurine-rich RNA sequences [ 47 ].…”

Section: General Dexd/h-box Helicases In Translationmentioning

confidence: 99%

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

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DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and translation. This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in eukaryotic translation initiation.

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Section: General Dexd/h-box Helicases In Translationmentioning

confidence: 99%

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Shen

Pelletier

2020

IJMS

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“…Inhibition of eIF4A is also a promising strategy for other cancer types including pancreatic cancer [21]. New amidino-rocaglate derivatives have recently been developed with an IC 50 value as low as 0.97 nM in MDA-MB-231 cells [22,23]. One rocaglate derivative, eFT226 (Zotatifin) has just entered a phase 1 clinical trial in patients with advanced solid tumors (NCT04092673) [24].…”

Section: Introductionmentioning

confidence: 99%

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

Howard

Estrada

Terrero

et al. 2020

Cancers

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The eukaryotic translation initiation factor 4F complex (eIF4F) is a potential chemotherapeutic target in triple-negative breast cancer (TNBC). This complex regulates cap-dependent translational initiation and consists of three core proteins: eIF4E, eIF4G, and eIF4A1. In this study, we focus on repositioning compounds as novel inhibitors of eIF4A1-mediated translation. In order to accomplish this goal, a modified synthetic reporter assay was established. More specifically, a (CGG)4 motif, which confers eIF4A dependency, was incorporated into the 5’-leader region of a luciferase-tdTomato lentiviral reporter construct. The Prestwick Chemical Library was then screened in multiple TNBC cell lines by measuring the tdTomato fluorescent intensity. We identified several cardiac glycosides as potential inhibitors of eIF4A1-mediated translation. Based on our studies, we find that cardiac glycosides inhibit the expression of eIF4A1. To identify a potential mechanism by which this was occurring, we utilized the Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our pursuits led us to the discovery that cardiac glycosides also decrease levels of c-MYC. Quantitative PCR confirmed that decreases in c-MYC and eIF4A were occurring at the transcriptional level. As such, disruption of the eIF4A1-c-MYC axis may be a viable approach in the treatment of TNBC. The novel combination of rocaglamide A and digoxin exhibited synergistic anti-cancer activity against TNBC cells in vitro. The findings in this study and others are important for formulating potential combination chemotherapies against eIF4A1 in vivo. Thus, drug repositioning may be one classical approach to successfully target eIF4A1 in TNBC patients.

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“…More recently, exploiting this molecular feature, effective pharmacological compounds directly targeting the translational machinery have been developed. Among them, we include ISRIB (integrated stress response inhibitor) that binds eIF2B [48,49] and amino-rocaglates that directly inhibit eIF4A [50]. Several other strategies for other initiation factors have been attempted or are in progress [8].…”

Section: Discussionmentioning

confidence: 99%

Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits

Pesce

Miluzio

Turcano

et al. 2020

Cells

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Eukaryotic initiation factor 6 (eIF6) is necessary for the nucleolar biogenesis of 60S ribosomes. However, most of eIF6 resides in the cytoplasm, where it acts as an initiation factor. eIF6 is necessary for maximal protein synthesis downstream of growth factor stimulation. eIF6 is an antiassociation factor that binds 60S subunits, in turn preventing premature 40S joining and thus the formation of inactive 80S subunits. It is widely thought that eIF6 antiassociation activity is critical for its function. Here, we exploited and improved our assay for eIF6 binding to ribosomes (iRIA) in order to screen for modulators of eIF6 binding to the 60S. Three compounds, eIFsixty-1 (clofazimine), eIFsixty-4, and eIFsixty-6 were identified and characterized. All three inhibit the binding of eIF6 to the 60S in the micromolar range. eIFsixty-4 robustly inhibits cell growth, whereas eIFsixty-1 and eIFsixty-6 might have dose- and cell-specific effects. Puromycin labeling shows that eIF6ixty-4 is a strong global translational inhibitor, whereas the other two are mild modulators. Polysome profiling and RT-qPCR show that all three inhibitors reduce the specific translation of well-known eIF6 targets. In contrast, none of them affect the nucleolar localization of eIF6. These data provide proof of principle that the generation of eIF6 translational modulators is feasible.

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Amidino-Rocaglates: A Potent Class of eIF4A Inhibitors

Cited by 52 publications

References 30 publications

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

Identification of Cardiac Glycosides as Novel Inhibitors of eIF4A1-Mediated Translation in Triple-Negative Breast Cancer Cells

Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits

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