Wortmannin Explained

Wortmannin, a steroid metabolite of the fungi Penicillium funiculosum, Talaromyces wortmannii, is a non-specific, covalent inhibitor of phosphoinositide 3-kinases (PI3Ks). It has an in vitro inhibitory concentration (IC50) of around 5 nM, making it a more potent inhibitor than LY294002, another commonly used PI3K inhibitor. It displays a similar potency in vitro for the class I, II, and III PI3K members although it can also inhibit other PI3K-related enzymes such as mTOR, DNA-PKcs, some phosphatidylinositol 4-kinases, myosin light chain kinase (MLCK) and mitogen-activated protein kinase (MAPK) at high concentrations[1] [2] Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 in the same range as for PI3K.[3] The half-life of wortmannin in tissue culture is about 10 minutes due to the presence of the highly reactive C20 carbon that is also responsible for its ability to covalently inactivate PI3K. Wortmannin is a commonly used cell biology reagent that has been used previously in research to inhibit DNA repair, receptor-mediated endocytosis and cell proliferation.[4] [5]

Phosphoinositide-3-kinase

Phosphoinositide-3-kinase (PI3K) activates an important cell survival signaling pathway, and constitutive activation is seen in ovarian, head and neck, urinary tract, cervical and small cell lung cancer. PI3K signaling is attenuated by the phosphatase activity of the tumor suppressor PTEN that is absent in a number of human cancers. Inhibiting PI3K presents the opportunity to inhibit a major cancer cell survival signaling pathway and to overcome the action of an important deleted tumor suppressor, providing antitumor activity and increased tumor sensitivity to a wide variety of drugs.

Wortmannin is a PI3K inhibitor; as such, it has detrimental influence on memory and impairs spatial learning abilities.[6] [7] [8]

Derivatives

Medicinal chemistry research has been conducted to identify wortmannin derivatives that are more stable, while not losing its therapeutic effect.[9]

Sonolisib

One of these, sonolisib (PX-866), has been shown to be an irreversible inhibitor of PI-3 kinase with efficacy when delivered orally. Sonolisib was put in a phase 1 clinical trial by Oncothyreon.[10] [11] The clinical development plan for sonolisib includes both standalone and combination therapy in major human cancers.[12] In 2010, sonolisib was starting 4 phase II trials for solid tumors.[13] The company gave an update on its phase 2 trials in Jun 2012.[14] Phase 1 results (with docetaxel) published Aug 2013.[15] In July 2014 published results of a phase 2 trial (for NSCLC) concluded : "The addition of PX-866 to docetaxel did not improve PFS, response rate, or OS in patients with advanced, refractory NSCLC without molecular preselection".[16] In Sept 2015 as Phase 2 trial for recurrent glioblastoma reported not meeting its primary endpoint.[17]

External links

Notes and References

  1. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD . Synthesis and function of 3-phosphorylated inositol lipids . Annual Review of Biochemistry . 70 . 535–602 . 2001 . 11395417 . 10.1146/annurev.biochem.70.1.535 .
  2. Book: Ferby I, Waga I, Kume K, Sakanaka C, Shimizu T . Platelet-Activating Factor and Related Lipid Mediators 2 . PAF-Induced MAPK Activation is Inhibited by Wortmannin in Neutrophils and Macrophages . Advances in Experimental Medicine and Biology . 416 . 321–6 . 1996 . 9131167 . 10.1007/978-1-4899-0179-8_51 . 978-1-4899-0181-1 .
  3. Liu Y, Jiang N, Wu J, Dai W, Rosenblum JS . Polo-like kinases inhibited by wortmannin. Labeling site and downstream effects . The Journal of Biological Chemistry . 282 . 4 . 2505–11 . January 2007 . 17135248 . 10.1074/jbc.M609603200 . free .
  4. Liu Y, Shreder KR, Gai W, Corral S, Ferris DK, Rosenblum JS . Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase . Chemistry & Biology . 12 . 1 . 99–107 . January 2005 . 15664519 . 10.1016/j.chembiol.2004.11.009 . free .
  5. Kim SH, Jang YW, Hwang P, Kim HJ, Han GY, Kim CW . The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats . Experimental & Molecular Medicine . 44 . 1 . 45–51 . January 2012 . 22056625 . 3277897 . 10.3858/emm.2012.44.1.004 .
  6. Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H, Nabeshima T . Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation . Molecular Psychiatry . 8 . 2 . 217–24 . February 2003 . 12610654 . 10.1038/sj.mp.4001215 . 21168835 .
  7. Jiang X, Tian Q, Wang Y, Zhou XW, Xie JZ, Wang JZ, Zhu LQ . Acetyl-L-carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol-3 kinase and protein kinase C . Journal of Neurochemistry . 118 . 5 . 864–78 . September 2011 . 21689104 . 10.1111/j.1471-4159.2011.07355.x . 45573586 .
  8. Kumar M, Bansal N . Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB . Behavioural Brain Research . 351 . 4–16 . October 2018 . 29807069 . 10.1016/j.bbr.2018.05.024 . 44121036 .
  9. Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G . Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling . Molecular Cancer Therapeutics . 3 . 7 . 763–72 . July 2004 . 10.1158/1535-7163.763.3.7 . 15252137 . free .
  10. Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT . The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures . Molecular Cancer Therapeutics . 6 . 9 . 2505–14 . September 2007 . 17766839 . 10.1158/1535-7163.MCT-06-0698 . 36657063 .
  11. http://www.tradingmarkets.com/news/stock-alert/onty_oncothyreon-presents-phase-1-data-for-px-866-and-px-478-at-asco-annual-meeting-973189.html PX-866 June 2010
  12. http://www.lifesciencesworld.com/news/view/73683 Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008
  13. News: ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor . 4 Nov 2010 .
  14. Web site: Oncothyreon Announces Presentation of PX-866 Clinical Data at American Association of Clinical Oncology Annual Meeting. June 2012 . 2016-03-17 . 2016-03-24 . https://web.archive.org/web/20160324125545/http://ir.oncothyreon.com/releasedetail.cfm?releaseid=679336 . dead .
  15. http://www.nature.com/bjc/journal/v109/n5/full/bjc2013474a.html A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours
  16. Levy B, Spira A, Becker D, Evans T, Schnadig I, Camidge DR, Bauman JE, Hausman D, Walker L, Nemunaitis J, Rudin CM, Halmos B, Bowles DW . A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer . Journal of Thoracic Oncology . 9 . 7 . 1031–1035 . July 2014 . 24926548 . 10.1097/JTO.0000000000000183 . free .
  17. Pitz MW, Eisenhauer EA, MacNeil MV, Thiessen B, Easaw JC, Macdonald DR, Eisenstat DD, Kakumanu AS, Salim M, Chalchal H, Squire J, Tsao MS, Kamel-Reid S, Banerji S, Tu D, Powers J, Hausman DF, Mason WP . Phase II study of PX-866 in recurrent glioblastoma . Neuro-Oncology . 17 . 9 . 1270–4 . September 2015 . 25605819 . 4588751 . 10.1093/neuonc/nou365 .

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