Wortmannin

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Wortmannin
Wortmannin chemical structure.png
Identifiers
CAS number 19545-26-7 YesY
PubChem 312145
ChemSpider 276037 N
ChEMBL CHEMBL428496 N
Jmol-3D images Image 1
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 (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Wortmannin, a steroid 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 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-PK, some phosphatidylinositol 4-kinases, myosin light chain kinase (MLCK) and mitogen-activated protein kinase (MAPK) at high concentrations [2],[3] Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 in the same range as for PI3K.[4] 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[citation needed].

Background: Phosphoinositide-3-kinase[edit]

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[edit]

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[edit]

  1. ^ Source: www.fermentek.co.il/wortmannin.htm
  2. ^ Vanhaesebroeck B et al., (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem.
  3. ^ Ferby I et al., 1996. Adv Exp Med Biol. PAF-induced MAPK activation is inhibited by wortmannin in neutrophils and macrophages.
  4. ^ Liu Y et al., 2007. J. Biol Chem 282(4): 2505-11 Polo-like Kinases Inhibited by Wortmannin: Labeling Site and Downstream Effects
  5. ^ Molecular Psychiatry (2003) 8, 217–224; Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation M Mizuno
  6. ^ 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
  7. ^ [1] lifesciencesworld news: Oncothyreon initiates Phase 1 trial of PX-866 cancer compound

External links[edit]

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