Wortmannin

Source: Wikipedia, the free encyclopedia.
Wortmannin
Names
IUPAC name
1α-(Methoxymethyl)-3,7,17-trioxo-2-oxa-6,4-(epoxymetheno)androsta-5,8-dien-11α-yl acetate
Systematic IUPAC name
(1S,6bR,9aS,11R,11bR)-1-(Methoxymethyl)-9a,11b-dimethyl-3,6,9-trioxo-1,6,6b,7,8,9,9a,10,11,11b-decahydro-3H-furo[4,3,2-de]indeno[4,5-h][2]benzopyran-11-yl acetate
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.112.065 Edit this at Wikidata
IUPHAR/BPS
UNII
  • 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
  • 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 428.437 g·mol−1
Melting point 238 to 242 °C (460 to 468 °F; 511 to 515 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Wortmannin, a steroid metabolite of the fungi

myosin light chain kinase (MLCK) and mitogen-activated protein kinase (MAPK) at high concentrations[1][2] Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 in the same range as for PI3K.[3] 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.[4][5]

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. PI3K signaling is attenuated by the phosphatase activity of the tumor suppressor PTEN that is absent in a number of human cancers. Inhibiting PI3K 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

PI3K inhibitor; as such, it has detrimental influence on memory and impairs spatial learning abilities.[6][7][8]

Derivatives

Medicinal chemistry research has been conducted to identify wortmannin derivatives that are more stable, while not losing its therapeutic effect.[9]

Sonolisib

Chemical structure of sonolisib

One of these, sonolisib (PX-866), has been shown to be an

solid tumors.[14] The company gave an update on its phase 2 trials in Jun 2012.[15] Phase 1 results (with docetaxel) published Aug 2013.[16] 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".[17] In Sept 2015 as Phase 2 trial for recurrent glioblastoma reported not meeting its primary endpoint.[18]

References

  1. PMID 11395417
    .
  2. PMID 9131167
    .
  3. PMID 17135248
    .
  4. PMID 15664519
    .
  5. PMID 22056625
    .
  6. S2CID 21168835
    .
  7. S2CID 45573586
    .
  8. S2CID 44121036
    .
  9. PMID 15252137
    .
  10. S2CID 36657063
    .
  11. ^ PX-866 June 2010
  12. ^ Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
  13. ^ Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008 lifesciencesworld news
  14. ^ "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010.
  15. ^ Oncothyreon Announces Presentation of PX-866 Clinical Data at American Association of Clinical Oncology Annual Meeting. June 2012
  16. ^ A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours
  17. PMID 24926548
    .
  18. PMID 25605819
    .

External links

Media related to Wortmannin at Wikimedia Commons

Retrieved from "https://en.wikipedia.org/w/index.php?title=Wortmannin&oldid=1211955691"