Wortmannin

Wortmannin
Names
Preferred 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
CAS Number
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.112.065 Edit this at Wikidata
PubChem CID
UNII
InChI
  • 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
SMILES
  • 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
Chemical formula
 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).
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Infobox references

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[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 irreversible inhibitor of PI-3 kinase with efficacy when delivered orally. Sonolisib was put in a phase 1 clinical trial by Oncothyreon.[10][11][12] The clinical development plan for sonolisib includes both standalone and combination therapy in major human cancers.[13] In 2010, sonolisib was starting 4 phase II trials for 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. ↑ Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD (2001). "Synthesis and function of 3-phosphorylated inositol lipids". Annual Review of Biochemistry. 70: 535–602. doi:10.1146/annurev.biochem.70.1.535. PMID 11395417.
  2. ↑ Ferby I, Waga I, Kume K, Sakanaka C, Shimizu T (1996). "PAF-induced MAPK activation is inhibited by wortmannin in neutrophils and macrophages". Advances in Experimental Medicine and Biology. 416: 321–6. doi:10.1007/978-1-4899-0179-8_51. PMID 9131167.
  3. ↑ Liu Y, Jiang N, Wu J, Dai W, Rosenblum JS (January 2007). "Polo-like kinases inhibited by wortmannin. Labeling site and downstream effects". The Journal of Biological Chemistry. 282 (4): 2505–11. doi:10.1074/jbc.M609603200. PMID 17135248.
  4. ↑ Liu Y, Shreder KR, Gai W, Corral S, Ferris DK, Rosenblum JS (January 2005). "Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase". Chemistry & Biology. 12 (1): 99–107. doi:10.1016/j.chembiol.2004.11.009. PMID 15664519.
  5. ↑ Kim SH, Jang YW, Hwang P, Kim HJ, Han GY, Kim CW (January 2012). "The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats". Experimental & Molecular Medicine. 44 (1): 45–51. doi:10.3858/emm.2012.44.1.004. PMC 3277897. PMID 22056625.
  6. ↑ Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H, Nabeshima T (February 2003). "Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation". Molecular Psychiatry. 8 (2): 217–24. doi:10.1038/sj.mp.4001215. PMID 12610654.
  7. ↑ Jiang X, Tian Q, Wang Y, Zhou XW, Xie JZ, Wang JZ, Zhu LQ (September 2011). "Acetyl-L-carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol-3 kinase and protein kinase C". Journal of Neurochemistry. 118 (5): 864–78. doi:10.1111/j.1471-4159.2011.07355.x. PMID 21689104.
  8. ↑ Kumar M, Bansal N (October 2018). "Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB". Behavioural Brain Research. 351: 4–16. doi:10.1016/j.bbr.2018.05.024. PMID 29807069.
  9. ↑ Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G (July 2004). "Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling". Molecular Cancer Therapeutics. 3 (7): 763–72. PMID 15252137.
  10. ↑ Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT (September 2007). "The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures". Molecular Cancer Therapeutics. 6 (9): 2505–14. doi:10.1158/1535-7163.MCT-06-0698. PMID 17766839.
  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. ↑ Levy B, Spira A, Becker D, Evans T, Schnadig I, Camidge DR, et al. (July 2014). "A randomized, phase 2 trial of Docetaxel with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic non-small-cell lung cancer". Journal of Thoracic Oncology. 9 (7): 1031–1035. doi:10.1097/JTO.0000000000000183. PMID 24926548.
  18. ↑ Pitz MW, Eisenhauer EA, MacNeil MV, Thiessen B, Easaw JC, Macdonald DR, et al. (September 2015). "Phase II study of PX-866 in recurrent glioblastoma". Neuro-Oncology. 17 (9): 1270–4. doi:10.1093/neuonc/nou365. PMC 4588751. PMID 25605819.
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