Wortmannin

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.

Derivatives

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

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. The clinical development plan for sonolisib includes both standalone and combination therapy in major human cancers. In 2010, sonolisib was starting 4 phase II trials for solid tumors. The company gave an update on its phase 2 trials in Jun 2012. Phase 1 results (with docetaxel) published Aug 2013. 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". In Sept 2015 as Phase 2 trial for recurrent glioblastoma reported not meeting its primary endpoint.

References

References

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4. (January 2005). "Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase". Chemistry & Biology.
5. (January 2012). "The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats". Experimental & Molecular Medicine.
6. (February 2003). "Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation". Molecular Psychiatry.
7. (September 2011). "Acetyl-L-carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol-3 kinase and protein kinase C". Journal of Neurochemistry.
8. (October 2018). "Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB". Behavioural Brain Research.
9. (July 2004). "Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling". Molecular Cancer Therapeutics.
10. (September 2007). "The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures". Molecular Cancer Therapeutics.
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]{{Dead link. (May 2024)
12. {{ClinicalTrialsGov. NCT00726583. Phase I Trial of Oral PX-866
13. [http://www.lifesciencesworld.com/news/view/73683 Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008] {{Webarchive. link. (2017-10-21 lifesciencesworld news)
14. (4 Nov 2010 }}{{Dead link). "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor".
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16. [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]
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18. (September 2015). "Phase II study of PX-866 in recurrent glioblastoma". Neuro-Oncology.