Abstract 2698: eFT226, a potent and selective inhibitor of eIF4A, is efficacious in preclinical models of lymphoma

Thompson, P.; Eam, Boreth; Young, Nathan Paul; Fish, Sarah; Chen, Joan; Barrera, María Laura de la; Howard, Haleigh; Sung, Eric; Parra, Ana; Staunton, Jocelyn; Chiang, Gary G.; Wegerski, Christopher J.; Nevarez, Andres; Clarine, Jeff; Sperry, Samuel; Xiang, Alan X.; Tran, Chinh C.; Nilewski, Christian; Packard, Garrick K.; Michels, Theodore; Sprengeler, Paul A.; Ernst, Justin T.; Reich, Siegfried; Webster, Kevin R.

doi:10.1158/1538-7445.sabcs18-2698

Cited by 4 publications

(3 citation statements)

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“…Manipulation of SG and related RNA biology is common among coronaviridae 34 – 36 and stress granule formation is thought to be a primarily antiviral response. The promotion of G3BP aggregation by eIF4A inhibitors 28 , 37 may partially explain their antiviral activity (see below).…”

Section: Mainmentioning

confidence: 99%

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gordon

Jang

Bouhaddou

et al. 2020

Nature

3,926

157

5,576

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The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

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Section: Mainmentioning

confidence: 99%

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

Gordon

Jang

Bouhaddou

et al. 2020

Nature

3,926

157

5,576

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“…SGs are induced by protein kinase R (PKR)-mediated phosphorylation of eIF2α upon viral dsRNA recognition 57 . Promoting G3BP aggregation via the eIF4A inhibitor Zotatafin 58,59 or reducing SG disassembly by Silmitasertib inhibition of CK2 60 warrant investigation for treatment of SARS-CoV-2. The mTOR inhibitor rapamycin disrupts the binding of LARP1 to mTORC1 61 and has been shown to reduce MERS infection by ~60% in vitro 62 , another drug that could be tested for repurposing.…”

Section: Sars-cov-2 Interacts With Multiple Innate Immune Pathwaysmentioning

confidence: 99%

A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

Gordon¹,

Jang²,

Bouhaddou³

et al. 2020

Preprint

431

586

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ABSTRACTAn outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.

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“…Once viral dsRNA recognised the protein kinase R (PKR)mediated phosphorylation of eIF2α lead to induction of SGs [120]. Zotatafin (eIF4A inhibitor) promote the aggregation of G3BP [121,122] or inhibition of CK2 by Silmitasertib [123] which lead to disassembly of SG warranted studies for SARS-CoV-2 treatment [34].…”

Section: Immune Responsementioning

confidence: 99%