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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. PI-3-K signaling is attenuated by the phosphatase activity of the tumor suppressor PTEN that is absent in a number of human cancers. Inhibiting PI-3-K 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 known and potent PI3K inhibitor; as such, it was shown to have detrimental influence on memory and impair spatial learning abilities.[5][citation needed]
Derivates
In order to stabilize the Wortmannin molecule while not losing its therapeutic effect, numerous derivates were synthesized from Wortmannin[6]
PX-866
One of these, PX-866, has been shown to be a novel, potent, irreversible, inhibitor of PI-3 kinase with efficacy when delivered orally. PX-866 was put in a phase 1 clinical trial by Oncothyreon company.[7][8][9] The clinical development plan for PX-866 includes both standalone and combination therapy in major human cancers.[10] In 2010 PX-866 was starting 4 phase II trials for solid tumours.[11] The company gave an update on its phase 2 trials in Jun 2012.[12] Phase 1 results (with docetaxel) published Aug 2013.[13] 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".[14] In Sept 2015 as Phase 2 trial for recurrent glioblastoma reported not meeting its primary endpoint.[15]
This section needs to be updated. Please help update this article to reflect recent events or newly available information.(December 2015)
^Vanhaesebroeck B et al., (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem.
^Ferby I et al., 1996. Adv Exp Med Biol. PAF-induced MAPK activation is inhibited by wortmannin in neutrophils and macrophages.
^Liu Y et al., 2007. J. Biol Chem 282(4): 2505-11 Polo-like Kinases Inhibited by Wortmannin: Labeling Site and Downstream Effects
^Molecular Psychiatry (2003) 8, 217–224; Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation
M Mizuno
^The discovery of PX-866: Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling, Nathan T. Ihle et al., Mol Cancer Ther. 2004;3:763-772
^Howes, AL; Chiang, GG; Lang, ES; Ho, CB; Powis, G; Vuori, K; Abraham, RT (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. 6 (9): 2505–14. doi:10.1158/1535-7163.MCT-06-0698. PMID17766839.
