Chemistry:Apilimod
Apilimod (STA-5326) is a drug that was initially identified as an inhibitor of production of the interleukins IL-12 and IL-23, and developed for the oral treatment of autoimmune conditions such as Crohn's disease and rheumatoid arthritis,[1] though clinical trial results were disappointing and development for these applications was not continued.[2][3]
Subsequently, it was discovered that apilimod has an additional mode of action, as an inhibitor of the lipid kinase enzyme PIKfyve.[4][5] PIKfyve makes two lipids, PtdIns5P and PtdIns(3,5)P2, whose syntheses are efficiently and similarly inhibited by apilimod (ID50 = 0.4 nM) in in vitro assays. Administration of apilimod (100 nM; 60 min) in human embryonic kidney cells powerfully reduces levels of both PtdIns5P and PtdIns(3,5)P2.[6]
Recently apilimod has been repurposed as a potential antiviral and anti-cancer drug, with possible applications in the treatment of non-Hodgkin lymphoma as well as viral diseases such as Ebola virus disease, Lassa fever and COVID-19.[7][8][9][10][11]
References
- ↑ "Drug evaluation: apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency". IDrugs 10 (1): 53–9. January 2007. PMID 17187316.
- ↑ "Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease". Inflammatory Bowel Diseases 16 (7): 1209–18. July 2010. doi:10.1002/ibd.21159. PMID 19918967.
- ↑ "Brief report: a phase IIa, randomized, double-blind, placebo-controlled trial of apilimod mesylate, an interleukin-12/interleukin-23 inhibitor, in patients with rheumatoid arthritis". Arthritis and Rheumatism 64 (6): 1750–5. June 2012. doi:10.1002/art.34339. PMID 22170479.
- ↑ "Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells". Molecular and Cellular Biology 19 (1): 623–634. 1999. doi:10.1128/mcb.19.1.623. PMID 9858586.
- ↑ "PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling". Chemistry & Biology 20 (7): 912–21. July 2013. doi:10.1016/j.chembiol.2013.05.010. PMID 23890009.
- ↑ "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". PLOS ONE 13 (9). September 2018. doi:10.1371/journal.pone.0204532. PMID 30240452. Bibcode: 2018PLoSO..1304532S.
- ↑ "Identification of apilimod as a first-in-class PIKfyve kinase inhibitor for treatment of B-cell non-Hodgkin lymphoma". Blood 129 (13): 1768–1778. March 2017. doi:10.1182/blood-2016-09-736892. PMID 28104689.
- ↑ "The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection". PLOS Neglected Tropical Diseases 11 (4). April 2017. doi:10.1371/journal.pntd.0005540. PMID 28403145.
- ↑ "Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses". Journal of Virology 93 (8). April 2019. doi:10.1128/JVI.02185-18. PMID 30700611.
- ↑ "Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations". Toxicology and Applied Pharmacology 383. November 2019. doi:10.1016/j.taap.2019.114771. PMID 31628917.
- ↑ "Researchers use live virus to identify 30 existing drugs that could treat COVID-19 | SBP". https://www.sbpdiscovery.org/news/researchers-use-live-virus-to-identify-30-existing-drugs-could-treat-covid-19.
 |  |
