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 , Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 in the same range as for PI3K. 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. 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 , Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 in the same range as for PI3K. 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. 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. In order to stabilize the Wortmannin molecule while not losing its therapeutic effect, numerous derivates were synthesized from Wortmannin One of these, PX-866 (now 'Sonolisib'), 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. The clinical development plan for PX-866 includes both standalone and combination therapy in major human cancers. In 2010 PX-866 was starting 4 phase II trials for solid tumours. 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.