| Wortmannin | |
|---|---|
 |
|
| Identifiers | |
| CAS number | 19545-26-7 |
| PubChem | 5691 |
| SMILES |
CC(=O)OC1CC2(C(CCC2=O)C3=C1C4 (C(OC(=O)C5=COC(=C54)C3=O)COC)C)C
|
| Properties | |
| Molecular formula | C23H24O8 |
| Molar mass | 428.43186 |
| Melting point |
238-242°C |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) | |
| Infobox references | |
Wortmannin, a furanosteroid metabolite of the fungi Penicillium funiculosum, Talaromyces (Penicillium) wortmannii[1], is a 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
Contents |
Background: [5] Phosphoinositide-3-kinase
Phosphoinositide-3-kinase (PI-3-K) 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 PI-3-K inhibitor; as such, it was shown to have enhancing influence on memory and impair learning abilities.
Derivates
In order to stabilize the Wortmannin molecule while not losing its therapeutic effect, numerous derivates were synthesized from Wortmannin[6]
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 is currently 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.[7]
References
- ^ Source: www.fermentek.co.il/wortmannin.htm
- ^ 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
- ^ Source: [1]
- ^ 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
- ^ [2] lifesciencesworld news: Oncothyreon initiates Phase 1 trial of PX-866 cancer compound
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