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]
Derivativesedit
Medicinal chemistry research has been conducted to identify wortmannin derivatives that are more stable, while not losing its therapeutic effect.[9]
Sonolisibedit
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]
Referencesedit
^Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, et al. (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.
^Ferby I, Waga I, Kume K, Sakanaka C, Shimizu T (1996). "PAF-Induced MAPK Activation is Inhibited by Wortmannin in Neutrophils and Macrophages". Platelet-Activating Factor and Related Lipid Mediators 2. Advances in Experimental Medicine and Biology. Vol. 416. pp. 321–6. doi:10.1007/978-1-4899-0179-8_51. ISBN978-1-4899-0181-1. PMID 9131167.
^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.
^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.
^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. PMC3277897. PMID 22056625.
^Mizuno M, Yamada K, Takei N, Tran MH, He J, Nakajima A, et al. (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. S2CID 21168835.
^Jiang X, Tian Q, Wang Y, Zhou XW, Xie JZ, Wang JZ, et al. (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. S2CID 45573586.
^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. S2CID 44121036.
^Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, et al. (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. doi:10.1158/1535-7163.763.3.7. PMID 15252137.
^Howes AL, Chiang GG, Lang ES, Ho CB, Powis G, Vuori K, et al. (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. S2CID 36657063.
^Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
^Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008 lifesciencesworld news
^"ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010.[permanent dead link]
^. Archived from the original on 2016-03-24. Retrieved 2016-03-17.
^A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours
^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.
^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. PMC4588751. PMID 25605819.
wortmannin, steroid, metabolite, fungi, penicillium, funiculosum, talaromyces, wortmannii, specific, covalent, inhibitor, phosphoinositide, kinases, pi3ks, vitro, inhibitory, concentration, ic50, around, making, more, potent, inhibitor, than, ly294002, another. 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 Wortmannin Names IUPAC name 1a Methoxymethyl 3 7 17 trioxo 2 oxa 6 4 epoxymetheno androsta 5 8 dien 11a 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 CAS Number 19545 26 7 Y 3D model JSmol Interactive image ChEBI CHEBI 52289 ChEMBL ChEMBL428496 N ChemSpider 276037 N ECHA InfoCard 100 112 065 IUPHAR BPS 6060 PubChem CID 312145 UNII XVA4O219QW Y CompTox Dashboard EPA DTXSID8040642 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 NKey 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 C 23H 24O 8 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 Y N Infobox references Contents 1 Phosphoinositide 3 kinase 2 Derivatives 2 1 Sonolisib 3 References 4 External linksPhosphoinositide 3 kinase editPhosphoinositide 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 editMedicinal chemistry research has been conducted to identify wortmannin derivatives that are more stable while not losing its therapeutic effect 9 Sonolisib edit nbsp 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 edit Vanhaesebroeck B Leevers SJ Ahmadi K Timms J Katso R Driscoll PC et al 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 Ferby I Waga I Kume K Sakanaka C Shimizu T 1996 PAF Induced MAPK Activation is Inhibited by Wortmannin in Neutrophils and Macrophages Platelet Activating Factor and Related Lipid Mediators 2 Advances in Experimental Medicine and Biology Vol 416 pp 321 6 doi 10 1007 978 1 4899 0179 8 51 ISBN 978 1 4899 0181 1 PMID 9131167 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 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 amp Biology 12 1 99 107 doi 10 1016 j chembiol 2004 11 009 PMID 15664519 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 amp Molecular Medicine 44 1 45 51 doi 10 3858 emm 2012 44 1 004 PMC 3277897 PMID 22056625 Mizuno M Yamada K Takei N Tran MH He J Nakajima A et al 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 S2CID 21168835 Jiang X Tian Q Wang Y Zhou XW Xie JZ Wang JZ et al 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 S2CID 45573586 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 NFkB Behavioural Brain Research 351 4 16 doi 10 1016 j bbr 2018 05 024 PMID 29807069 S2CID 44121036 Ihle NT Williams R Chow S Chew W Berggren MI Paine Murrieta G et al 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 doi 10 1158 1535 7163 763 3 7 PMID 15252137 Howes AL Chiang GG Lang ES Ho CB Powis G Vuori K et al 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 S2CID 36657063 PX 866 June 2010 permanent dead link Clinical trial number NCT00726583 for Phase I Trial of Oral PX 866 at ClinicalTrials gov Oncothyreon initiates Phase 1 trial of PX 866 cancer compound 17 06 2008 lifesciencesworld news ONTY Starts Four Phase II Trial Program With Its Oral PI3K Inhibitor 4 Nov 2010 permanent dead link Oncothyreon Announces Presentation of PX 866 Clinical Data at American Association of Clinical Oncology Annual Meeting June 2012 Archived from the original on 2016 03 24 Retrieved 2016 03 17 A multicenter phase 1 study of PX 866 in combination with docetaxel in patients with advanced solid tumours 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 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 External links edit nbsp Media related to Wortmannin at Wikimedia Commons Wortmannin bound to proteins in the PDB Retrieved from https en wikipedia org w index php title Wortmannin amp oldid 1222658862, wikipedia, wiki, book, books, library,
