Apilimod Explained

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]

Notes and References

  1. Billich A . 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 . 17187316 .
  2. Sands BE, Jacobson EW, Sylwestrowicz T, Younes Z, Dryden G, Fedorak R, Greenbloom S . 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 . 19918967 . 10.1002/ibd.21159 . 26012456 . free .
  3. Krausz S, Boumans MJ, Gerlag DM, Lufkin J, van Kuijk AW, Bakker A, de Boer M, Lodde BM, Reedquist KA, Jacobson EW, O'Meara M, Tak PP . 6 . 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 . 22170479 . 10.1002/art.34339 .
  4. Shisheva A, Sbrissa D, Ikonomov O . 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 . 9858586 . 10.1128/mcb.19.1.623 . 83920 . free .
  5. Cai X, Xu Y, Cheung AK, Tomlinson RC, Alcázar-Román A, Murphy L, Billich A, Zhang B, Feng Y, Klumpp M, Rondeau JM, Fazal AN, Wilson CJ, Myer V, Joberty G, Bouwmeester T, Labow MA, Finan PM, Porter JA, Ploegh HL, Baird D, De Camilli P, Tallarico JA, Huang Q . 6 . 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 . 23890009 . 4878021 . 10.1016/j.chembiol.2013.05.010 .
  6. Sbrissa D, Naisan G, Ikonomov OC, Shisheva A . 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 . e0204532 . September 2018 . 30240452 . 10.1371/journal.pone.0204532. 6150535 . 2018PLoSO..1304532S . free .
  7. Gayle S, Landrette S, Beeharry N, Conrad C, Hernandez M, Beckett P, Ferguson SM, Mandelkern T, Zheng M, Xu T, Rothberg J, Lichenstein H . 6 . 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 . 28104689 . 5766845 . 10.1182/blood-2016-09-736892 .
  8. Nelson EA, Dyall J, Hoenen T, Barnes AB, Zhou H, Liang JY, Michelotti J, Dewey WH, DeWald LE, Bennett RS, Morris PJ, Guha R, Klumpp-Thomas C, McKnight C, Chen YC, Xu X, Wang A, Hughes E, Martin S, Thomas C, Jahrling PB, Hensley LE, Olinger GG, White JM . 6 . The phosphatidylinositol-3-phosphate 5-kinase inhibitor apilimod blocks filoviral entry and infection . PLOS Neglected Tropical Diseases . 11 . 4 . e0005540 . April 2017 . 28403145 . 5402990 . 10.1371/journal.pntd.0005540 . free .
  9. Hulseberg CE, Fénéant L, Szymańska-de Wijs KM, Kessler NP, Nelson EA, Shoemaker CJ, Schmaljohn CS, Polyak SJ, White JM . 6 . Arbidol and Other Low-Molecular-Weight Drugs That Inhibit Lassa and Ebola Viruses . Journal of Virology . 93 . 8 . April 2019 . 30700611 . 6450122 . 10.1128/JVI.02185-18 .
  10. Ikonomov OC, Sbrissa D, Shisheva A . Small molecule PIKfyve inhibitors as cancer therapeutics: Translational promises and limitations . Toxicology and Applied Pharmacology . 383 . 114771 . November 2019 . 31628917 . 10.1016/j.taap.2019.114771 . free .
  11. Web site: Researchers use live virus to identify 30 existing drugs that could treat COVID-19 SBP. www.sbpdiscovery.org. 2020-04-20.

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