Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation

Sbrissa, Diego; Naisan, Ghassan; Ikonomov, Ognian C.; Shisheva, Assia

doi:10.1371/journal.pone.0204532

Cited by 28 publications

(35 citation statements)

References 66 publications

(138 reference statements)

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“…Apilimod has been found to be well tolerated in humans, exhibiting a desirable safety profile at doses of up to 125 mg twice daily 2,48 and a peak serum concentration of 0.265 ± 0.183 μM, indicating that therapeutic dosing may be achieved in patients at concentrations likely to promote antiviral activity. Apilimod has been evaluated in phase II clinical trials for the treatment of active Crohn's disease, rheumatoid arthritis and common variable immunodeficiency 2,3 , and in phase I studies for the treatment of follicular lymphoma 49 . Apilimod also efficiently inhibits Ebola virus, Lassa virus and Marburg virus in human cell lines, underscoring its potential broad-spectrum antiviral activity 21,22 .…”

Section: Evaluation In Primary Human Cell Modelsmentioning

confidence: 99%

“…We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod [2][3][4] and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model.…”

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confidence: 99%

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Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Riva

Yuan

Yin

et al. 2020

Nature

746

769

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Summary The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19) 1 . The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod 2 – 4 , and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.

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Section: Evaluation In Primary Human Cell Modelsmentioning

confidence: 99%

mentioning

confidence: 99%

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Riva

Yuan

Yin

et al. 2020

Nature

746

769

View full text Add to dashboard Cite

show abstract

“…Finally, apilimod, a specific PIKfyve kinase inhibitor, was found to inhibit SARS-CoV-2 replication at an EC 50 concentration of 23 nM (Figure 3). Importantly, apilimod is found to be well tolerated in humans showing a desirable safety profile at doses of ≤ 125 mg BID, and the Cmax of this compound is 0.265 +/-0.183 µM (70 mg QD) 84,85 .…”

Section: Discussionmentioning

confidence: 99%

“…These data indicate that therapeutic dosing of apilimod in patients can achieve concentrations that are likely to promote antiviral activity. Apilimod has been evaluated in phase II clinical trials for the treatment of active Crohn's disease and rheumatoid arthritis (RA) 86 , and in additional phase II trials for the oral treatment of common variable immunodeficiency (CVID), but did not show efficacy for these indications 85,87 . In 2019, orphan drug designation was granted to apilimod in the U.S. for the treatment of follicular lymphoma 88 , with phase I clinical trials ongoing.…”

Section: Discussionmentioning

confidence: 99%

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Riva

Yuan

Yin

et al. 2020

Preprint

108

111

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The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 . To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDAapproved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

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“…Although mammalian cells have three PI 3-kinases, the Vps34 homologue (also known as PIK3C3) plays a critical role in endosomal trafficking and autophagy and forms the predominant pool of PI(3)P that is the precursor of PI(3,5)P 2 (Ikonomov et al, 2015). Recently, inhibition of cytosolic vacuolation in response to PIKfyve inhibition by bafilomycin was shown to involve attenuation of the elevated PI(3)P levels that generally accompany inhibition of PI(3,5)P 2 production (Sbrissa et al, 2018). These results highlight the importance of the V-ATPase in maintaining PI(3)P levels when PIKfyve is inhibited and suggest a potential role for PI(3)P in cytosolic vacuolation beyond acting as a PI(3,5)P 2 precursor.…”

Section: Can Pip Lipids Affect V-atpase Function In Vivo?mentioning

confidence: 99%

Regulation of V-ATPase Activity and Organelle pH by Phosphatidylinositol Phosphate Lipids

Banerjee

Kane

2020

Front. Cell Dev. Biol.

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Luminal pH and the distinctive distribution of phosphatidylinositol phosphate (PIP) lipids are central identifying features of organelles in all eukaryotic cells that are also critical for organelle function. V-ATPases are conserved proton pumps that populate and acidify multiple organelles of the secretory and the endocytic pathway. Complete loss of V-ATPase activity causes embryonic lethality in higher animals and conditional lethality in yeast, while partial loss of V-ATPase function is associated with multiple disease states. On the other hand, many cancer cells increase their virulence by upregulating V-ATPase expression and activity. The pH of individual organelles is tightly controlled and essential for function, but the mechanisms for compartment-specific pH regulation are not completely understood. There is substantial evidence indicating that the PIP content of membranes influences organelle pH. We present recent evidence that PIPs interact directly with subunit isoforms of the V-ATPase to dictate localization of V-ATPase subpopulations and participate in their regulation. In yeast cells, which have only one set of organelle-specific V-ATPase subunit isoforms, the Golgi-enriched lipid PI(4)P binds to the cytosolic domain of the Golgi-enriched a-subunit isoform Stv1, and loss of PI(4)P binding results in mislocalization of Stv1-containing V-ATPases from the Golgi to the vacuole/lysosome. In contrast, levels of the vacuole/lysosome-enriched signaling lipid PI(3,5)P 2 affect assembly and activity of V-ATPases containing the Vph1 a-subunit isoform. Mutations in the Vph1 isoform that disrupt the lipid interaction increase sensitivity to stress. These studies have decoded "zip codes" for PIP lipids in the cytosolic N-terminal domain of the a-subunit isoforms of the yeast V-ATPase, and similar interactions between PIP lipids and the V-ATPase subunit isoforms are emerging in higher eukaryotes. In addition to direct effects on the V-ATPase, PIP lipids are also likely to affect organelle pH indirectly, through interactions with other membrane transporters. We discuss direct and indirect effects of PIP lipids on organelle pH, and the functional consequences of the interplay between PIP lipid content and organelle pH.

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Apilimod, a candidate anticancer therapeutic, arrests not only PtdIns(3,5)P2 but also PtdIns5P synthesis by PIKfyve and induces bafilomycin A1-reversible aberrant endomembrane dilation

Cited by 28 publications

References 66 publications

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Regulation of V-ATPase Activity and Organelle pH by Phosphatidylinositol Phosphate Lipids

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