Wortmannin

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Wortmannin
200px
Identifiers
19545-26-7 YesY
ChEMBL ChEMBL428496 N
ChemSpider 276037 N
6060
Jmol 3D model Interactive image
PubChem 312145
  • InChI=1S/C23H24O8/c1-10(24)30-13-7-22(2)12(5-6-14(22)25)16-18(13)23(3)15(9-28-4)31-21(27)11-8-29-20(17(11)23)19(16)26/h8,12-13,15H,5-7,9H2,1-4H3/t12-,13+,15+,22-,23-/m0/s1 N
    Key: QDLHCMPXEPAAMD-QAIWCSMKSA-N N
  • InChI=1/C23H24O8/c1-10(24)30-13-7-22(2)12(5-6-14(22)25)16-18(13)23(3)15(9-28-4)31-21(27)11-8-29-20(17(11)23)19(16)26/h8,12-13,15H,5-7,9H2,1-4H3/t12-,13+,15+,22-,23-/m0/s1
    Key: QDLHCMPXEPAAMD-QAIWCSMKBP
  • O=C\3c2occ1C(=O)O[C@@H]([C@@](c12)(/C5=C/3[C@H]4[C@](C(=O)CC4)(C)C[C@H]5OC(=O)C)C)COC
Properties
C23H24O8
Molar mass 428.43186 g/mol
Melting point 238 to 242 °C (460 to 468 °F; 511 to 515 K)
Vapor pressure {{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Wortmannin, a steroid metabolite of the fungi Penicillium funiculosum, Talaromyces wortmannii,[1] 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 [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

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][12] Lua error in package.lua at line 80: module 'strict' not found.

References

  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. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ PX-866 June 2010
  9. ↑ Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
  10. ↑ Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008 lifesciencesworld news
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ http://www.drugrehab.in/2011/01/onty-starts-second-phase-iii-trial-of-pi3k-inhibitor-this-one-is-a-combo-with-merck-kgaas-erbitux/

External links

Vendors' product pages

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