Wortmannin: Difference between revisions

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| verifiedrevid = 393946468

| ImageFile = Wortmannin.svg

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| IUPACName = 1α-(Methoxymethyl)-3,7,17-trioxo-2-oxa-6,4-(epoxymetheno)androsta-5,8-dien-11α-yl acetate

| SystematicName = (1''S'',6b''R'',9a''S'',11''R'',11b''R'')-1-(Methoxymethyl)-9a,11b-dimethyl-3,6,9-trioxo-1,6,6b,7,8,9,9a,10,11,11b-decahydro-3''H''-furo[4,3,2-''de'']indeno[4,5-''h''][2]benzopyran-11-yl acetate

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| Section1 ={{Chembox Identifiers

| IUPHAR_ligand = 6060

| CASNo_Ref = {{cascite|correct|??}}

| CASNo =19545-26-7

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = XVA4O219QW

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 428496

| ChEBI = 52289

| PubChem = 312145

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 276037

| 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

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = QDLHCMPXEPAAMD-QAIWCSMKSA-N

| Section2 = {{Chembox Properties

| C=23 | H=24 | O=8

| Appearance =

| Density =

| MeltingPtC = 238 to 242

| MeltingPt_notes =

| BoilingPt =

| Solubility =

| Section3 = {{Chembox Hazards

| MainHazards =

| FlashPt =

| AutoignitionPt =

}}

'''Wortmannin''', a steroid metabolite of the fungi ''[[Penicillium funiculosum]]'', ''[[Talaromyces wortmannii]]'', is a non-specific, [[covalent]] inhibitor of [[phosphoinositide 3-kinase]]s (PI3Ks). It has an ''in vitro'' [[IC50|inhibitory concentration]] (''IC''₅₀) 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 PI 3-kinases|class I]], [[class II PI 3-kinases|II]], and [[Class III PI 3-kinase|III]] PI3K members although it can also inhibit other PI3K-related enzymes such as [[mTOR]], [[DNA-PKcs]], some [[phosphatidylinositol 4-kinase]]s, [[myosin light chain kinase]] (MLCK) and [[mitogen-activated protein kinase]] (MAPK) at high concentrations<ref name="pmid11395417">{{cite journal | vauthors = Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD | title = Synthesis and function of 3-phosphorylated inositol lipids | journal = Annual Review of Biochemistry | volume = 70 | pages = 535–602 | date = 2001 | pmid = 11395417 | doi = 10.1146/annurev.biochem.70.1.535 }}</ref><ref name="pmid9131167">{{cite book | vauthors = Ferby I, Waga I, Kume K, Sakanaka C, Shimizu T | title = Platelet-Activating Factor and Related Lipid Mediators 2 | chapter = PAF-Induced MAPK Activation is Inhibited by Wortmannin in Neutrophils and Macrophages | series = Advances in Experimental Medicine and Biology | volume = 416 | pages = 321–6 | date = 1996 | pmid = 9131167 | doi = 10.1007/978-1-4899-0179-8_51 | isbn = 978-1-4899-0181-1 }}</ref> Wortmannin has also been reported to inhibit members of the [[polo-like kinase]] family with ''IC''₅₀ in the same range as for PI3K.<ref name="pmid17135248">{{cite journal | vauthors = Liu Y, Jiang N, Wu J, Dai W, Rosenblum JS | title = Polo-like kinases inhibited by wortmannin. Labeling site and downstream effects | journal = The Journal of Biological Chemistry | volume = 282 | issue = 4 | pages = 2505–11 | date = January 2007 | pmid = 17135248 | doi = 10.1074/jbc.M609603200 | doi-access = free }}</ref> 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.<ref name="pmid15664519">{{cite journal | vauthors = Liu Y, Shreder KR, Gai W, Corral S, Ferris DK, Rosenblum JS | title = Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase | journal = Chemistry & Biology | volume = 12 | issue = 1 | pages = 99–107 | date = January 2005 | pmid = 15664519 | doi = 10.1016/j.chembiol.2004.11.009 | doi-access = free }}</ref><ref name="pmid22056625">{{cite journal | vauthors = Kim SH, Jang YW, Hwang P, Kim HJ, Han GY, Kim CW | title = The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats | journal = Experimental & Molecular Medicine | volume = 44 | issue = 1 | pages = 45–51 | date = January 2012 | pmid = 22056625 | pmc = 3277897 | doi = 10.3858/emm.2012.44.1.004 }}</ref>

==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.<ref name="pmid12610654">{{cite journal | vauthors = Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, Nawa H, Nabeshima T | title = Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation | journal = Molecular Psychiatry | volume = 8 | issue = 2 | pages = 217–24 | date = February 2003 | pmid = 12610654 | doi = 10.1038/sj.mp.4001215 | doi-access = | s2cid = 21168835 }}</ref><ref>{{cite journal | vauthors = Jiang X, Tian Q, Wang Y, Zhou XW, Xie JZ, Wang JZ, Zhu LQ | title = Acetyl-L-carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol-3 kinase and protein kinase C | journal = Journal of Neurochemistry | volume = 118 | issue = 5 | pages = 864–78 | date = September 2011 | pmid = 21689104 | doi = 10.1111/j.1471-4159.2011.07355.x | doi-access = | s2cid = 45573586 }}</ref><ref>{{cite journal | vauthors = Kumar M, Bansal N | title = Fasudil hydrochloride ameliorates memory deficits in rat model of streptozotocin-induced Alzheimer's disease: Involvement of PI3-kinase, eNOS and NFκB | journal = Behavioural Brain Research | volume = 351 | pages = 4–16 | date = October 2018 | pmid = 29807069 | doi = 10.1016/j.bbr.2018.05.024 | s2cid = 44121036 }}</ref>

==Derivatives==

[[Medicinal chemistry]] research has been conducted to identify wortmannin [[derivative (chemistry)|derivatives]] that are more stable, while not losing its therapeutic effect.<ref name="pmid15252137">{{cite journal | vauthors = 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 | title = Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling | journal = Molecular Cancer Therapeutics | volume = 3 | issue = 7 | pages = 763–72 | date = July 2004 | doi = 10.1158/1535-7163.763.3.7 | pmid = 15252137 | url = https://mct.aacrjournals.org/content/3/7/763.short | doi-access = free }}</ref>

===Sonolisib===

[[File:Sonolisib_structure.png|200px|thumb|right|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.<ref name=Howes2007>{{cite journal | vauthors = Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, Abraham RT | title = The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 9 | pages = 2505–14 | date = September 2007 | pmid = 17766839 | doi = 10.1158/1535-7163.MCT-06-0698 | doi-access = | s2cid = 36657063 }}</ref><ref name=Ph1-data2010>[http://www.tradingmarkets.com/news/stock-alert/onty_oncothyreon-presents-phase-1-data-for-px-866-and-px-478-at-asco-annual-meeting-973189.html PX-866 June 2010]{{Dead link|date=May 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref name=NCT00726583>{{ClinicalTrialsGov|NCT00726583|Phase I Trial of Oral PX-866}}</ref> The clinical development plan for sonolisib includes both standalone and combination therapy in major human cancers.<ref>[http://www.lifesciencesworld.com/news/view/73683 Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008] lifesciencesworld news</ref> In 2010, sonolisib was starting 4 phase II trials for [[solid tumor]]s.<ref>{{cite news |url=http://www.medicalnewstoday.com/articles/206625.php |title=ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor |date=4 Nov 2010 }}{{Dead link|date=May 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The company gave an update on its phase 2 trials in Jun 2012.<ref>{{Cite web |url=http://ir.oncothyreon.com/releasedetail.cfm?releaseid=679336 |title=Oncothyreon Announces Presentation of PX-866 Clinical Data at American Association of Clinical Oncology Annual Meeting. June 2012 |access-date=2016-03-17 |archive-date=2016-03-24 |archive-url=https://web.archive.org/web/20160324125545/http://ir.oncothyreon.com/releasedetail.cfm?releaseid=679336 |url-status=dead }}</ref> Phase 1 results (with docetaxel) published Aug 2013.<ref>[http://www.nature.com/bjc/journal/v109/n5/full/bjc2013474a.html A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours]</ref> 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".<ref>{{cite journal | vauthors = Levy B, Spira A, Becker D, Evans T, Schnadig I, Camidge DR, Bauman JE, Hausman D, Walker L, Nemunaitis J, Rudin CM, Halmos B, Bowles DW | title = 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 = Journal of Thoracic Oncology | volume = 9 | issue = 7 | pages = 1031–1035 | date = July 2014 | pmid = 24926548 | doi = 10.1097/JTO.0000000000000183 | doi-access = free }}</ref> In Sept 2015 as Phase 2 trial for recurrent [[glioblastoma]] reported not meeting its primary endpoint.<ref>{{cite journal | vauthors = Pitz MW, Eisenhauer EA, MacNeil MV, Thiessen B, Easaw JC, Macdonald DR, Eisenstat DD, Kakumanu AS, Salim M, Chalchal H, Squire J, Tsao MS, Kamel-Reid S, Banerji S, Tu D, Powers J, Hausman DF, Mason WP | title = Phase II study of PX-866 in recurrent glioblastoma | journal = Neuro-Oncology | volume = 17 | issue = 9 | pages = 1270–4 | date = September 2015 | pmid = 25605819 | pmc = 4588751 | doi = 10.1093/neuonc/nou365 }}</ref>

== References ==

{{Reflist|2}}

{{Commonscatinline|Wortmannin}}

* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=KWT Wortmannin bound to proteins] in the [[Protein Data Bank|PDB]]

[[Category:Acetate esters]]

[[Category:Furans]]

[[Category:Delta-lactones]]

[[Category:Phosphoinositide 3-kinase inhibitors]]

[[Category:Covalent inhibitors]]