Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors

Zhang, Wenhan; Chu, Jennifer; Cyr, Andrew M.; Yueh, Han; Brown, Lauren E.; Wang, Tony T.; Porco, John A.

doi:10.1021/jacs.9b06446

Cited by 32 publications

(27 citation statements)

References 79 publications

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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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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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“…In the present study, eIF4A was shown to be highly abundant in GBC tissues and cell lines. In addition, eIF4A inhibitor rocaglates CR-31 is currently the most potent translation initiation inhibitor that functions via eIF4A, and is well tolerated in vivo ( 20 , 21 ). Moreover, inhibitors of eIF4A, such as hippuristanol, can induce apoptosis of adult T-cell leukemia ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

“…Data are presented as the mean ± standard deviation. * P<0.05, ** P<0.01. eIF4A, eukaryotic translation initiation factor 4A; CR-31, CR-1-31B; GBC, gallbladder cancer; TRAIL, Tumor necrosis factor related apoptosis-inducing ligand; siRNA, small interfering RNA.and is well tolerated in vivo(20,21). Moreover, inhibitors of eIF4A, such as hippuristanol, can induce apoptosis of adult T-cell leukemia(22).…”

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confidence: 99%

Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP

Cao

Yang

et al. 2020

Oncol Rep

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Induction of the apoptosis of tumor cells is a promising therapeutic approach for the treatment of cancer. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel type of anticancer drug. However, gallbladder cancer cells (GBC) exhibit strong resistance to TRAIL. The aim of the present study was to assess the effect of rocaglate CR-1-31B (CR-31), an inhibitor of eukaryotic translation initiation factor 4A (eIF4A), on the sensitization of cells to TRAIL-induced apoptosis in TRAIL-resistant GBC. eIF4A was highly abundant in GBC tissues and cell lines (GBC-SD and SGC-996). GBC cells were treated using TRAIL and/or CR-31 and then apoptosis and TRAIL signaling were detected in vitro. CR-31 enhanced the sensitivity of TRAIL-resistant GBC cells, due to the CR-31-mediated eIF4A translational downregulation of c-FLIP and the subsequent activation of the caspase cascade. Furthermore, GBC-SD tumor xenografts models were established and the effects of CR-31 in vivo were assessed. CR-31 significantly reduced the growth and initiated the apoptosis of tumor cells, suggesting that CR-31 also increased sensitivity in vivo. Taken together, the results of the present study show that CR-31 treatment countered the resistance to TRAIL in GBC cells in vitro and in vivo. Therefore, eIF4A may serve as a novel therapeutic target and its combination with TRAIL-CR-31 as a therapy may serve as a novel strategy for GBC treatment.

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“…A chemical synthesis route of RocA was published in 1990 that allows the control of the absolute stereochemistry of the molecule class [ 81 ]. Since then, the synthesis has been further optimized and expanded to include a large number of modified rocaglates [ 82 ]. An example of such a non-naturally occurring rocaglate is CR-31-B.…”

Section: Eif4a Inhibitorsmentioning

confidence: 99%

Targeting the DEAD-Box RNA Helicase eIF4A with Rocaglates—A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

Taroncher-Oldenburg¹,

Müller

Obermann

et al. 2021

Microorganisms

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The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5′ untranslated regions (5′UTRs) onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5′UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

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Intercepted Retro-Nazarov Reaction: Syntheses of Amidino-Rocaglate Derivatives and Their Biological Evaluation as eIF4A Inhibitors

Abstract: OpenBU http://open.bu.edu Chemistry BU Open Access Articles 2019-08-14 Intercepted retro-Nazarov reaction: syntheses of amidino-rocaglate derivatives and their biologi...

Cited by 32 publications

References 79 publications

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

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

Targeting eIF4A using rocaglate CR‑1‑31B sensitizes gallbladder cancer cells to TRAIL‑mediated apoptosis through the translational downregulation of c‑FLIP

Targeting the DEAD-Box RNA Helicase eIF4A with Rocaglates—A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

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