Wortmannin

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
Wortmannin
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.112.065
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).

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.[6]

Derivates

In order to stabilize the Wortmannin molecule while not losing its therapeutic effect, numerous derivates were synthesized from Wortmannin[7]

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.[8][9][10] The clinical development plan for PX-866 includes both standalone and combination therapy in major human cancers.[11] In 2010 PX-866 was starting 4 phase II trials for solid tumours.[12] The company gave an update on its phase 2 trials in Jun 2012.[13] Phase 1 results (with docetaxel) published Aug 2013.[14] 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".[15] In Sept 2015 as Phase 2 trial for recurrent glioblastoma reported not meeting its primary endpoint.[16]

References

  1. ^ Vanhaesebroeck B et al., (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem.
  2. ^ Ferby I et al., 1996. Adv Exp Med Biol. PAF-induced MAPK activation is inhibited by wortmannin in neutrophils and macrophages.
  3. ^ Liu Y et al., 2007. J. Biol Chem 282(4): 2505-11 Polo-like Kinases Inhibited by Wortmannin: Labeling Site and Downstream Effects
  4. ^ Liu Y, Shreder KR, Gai W, Corral S, Ferris DK, Rosenblum JS. Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase. Chem Biol. 2005;12:99–107.
  5. ^ Sang-Hoon Kim, Young-Woo Jang, Patrick Hwang, Hyun-Jung Kim, Gi-Yeon Han, and Chan-Wha Kim; The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats; Exp Mol Med. 2012 Jan 31; 44(1): 45–51.
  6. ^ Molecular Psychiatry (2003) 8, 217–224; Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation M Mizuno
  7. ^ 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
  8. ^ Howes, AL; Chiang, GG; Lang, ES; Ho, CB; Powis, G; Vuori, K; Abraham, RT (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.
  9. ^ PX-866 June 2010
  10. ^ Clinical trial number NCT00726583 for "Phase I Trial of Oral PX-866" at ClinicalTrials.gov
  11. ^ Oncothyreon initiates Phase 1 trial of PX-866 cancer compound. 17/06/2008 lifesciencesworld news
  12. ^ "ONTY Starts Four-Phase II Trial Program With Its Oral PI3K Inhibitor". 4 Nov 2010.
  13. ^ Oncothyreon Announces Presentation of PX-866 Clinical Data at American Association of Clinical Oncology Annual Meeting. June 2012
  14. ^ A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours
  15. ^ 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 (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". J Thorac Oncol. 9 (7): 1031–5. doi:10.1097/JTO.0000000000000183. PMID 24926548.
  16. ^ 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 (2015). "Phase II study of PX-866 in recurrent glioblastoma". Neuro Oncol. 17 (9): 1270–4. doi:10.1093/neuonc/nou365. PMC 4588751. PMID 25605819.

External links

Aldol reaction

The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry.

Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carbonyl compounds (the original experiments used aldehydes) to form a new β-hydroxy carbonyl compound. These products are known as aldols, from the aldehyde + alcohol, a structural motif seen in many of the products. Aldol structural units are found in many important molecules, whether naturally occurring or synthetic.

For example, the aldol reaction has been used in the large-scale production of the commodity chemical pentaerythritol

and the synthesis of the heart disease drug Lipitor (atorvastatin, calcium salt).The aldol reaction unites two relatively simple molecules into a more complex one. Increased complexity arises because up to two new stereogenic centers (on the α- and β-carbon of the aldol adduct, marked with asterisks in the scheme below) are formed. Modern methodology is capable of not only allowing aldol reactions to proceed in high yield but also controlling both the relative and absolute configuration of these stereocenters. This ability to selectively synthesize a particular stereoisomer is significant because different stereoisomers can have very different chemical and biological properties.

For example, stereogenic aldol units are especially common in polyketides, a class of molecules found in biological organisms. In nature, polyketides are synthesized by enzymes that effect iterative Claisen condensations. The 1,3-dicarbonyl products of these reactions can then be variously derivatized to produce a wide variety of interesting structures. Often, such derivitization involves the reduction of one of the carbonyl groups, producing the aldol subunit. Some of these structures have potent biological properties: the immunosuppressant FK506, the anti-tumor agent discodermolide, or the antifungal agent amphotericin B, for example. Although the synthesis of many such compounds was once considered nearly impossible, aldol methodology has allowed their efficient synthesis in many cases.

A typical modern aldol addition reaction, shown above, might involve the nucleophilic addition of a ketone enolate to an aldehyde. Once formed, the aldol product can sometimes lose a molecule of water to form an α,β-unsaturated carbonyl compound. This is called aldol condensation. A variety of nucleophiles may be employed in the aldol reaction, including the enols, enolates, and enol ethers of ketones, aldehydes, and many other carbonyl compounds. The electrophilic partner is usually an aldehyde or ketone (many variations, such as the Mannich reaction, exist). When the nucleophile and electrophile are different, the reaction is called a crossed aldol reaction; on the converse, when the nucleophile and electrophile are the same, the reaction is called an aldol dimerization.

C2 domain

A C2 domain is a protein structural domain involved in targeting proteins to cell membranes. The typical version (PKC-C2) has a beta-sandwich composed of 8 β-strands that co-ordinates two or three calcium ions, which bind in a cavity formed by the first and final loops of the domain, on the membrane binding face. Many other C2 domain families don't have calcium binding activity.

CDC5L

Cell division cycle 5-like protein is a protein that in humans is encoded by the CDC5L gene.

Fermentek

Fermentek Ltd. is a biotechnological company in the Atarot industrial zone of Jerusalem, Israel. It specializes in the research, development and manufacture of biologically active, natural products isolated from microorganisms as well as from other natural sources such as plants and algae.

The main microorganisms used are nonpathogenic actinomycetes, Nocardia and Streptomycetes. The fungi used are: Penicillium, Aspergillus, Fusarium and the like. None of these is a human pathogen.

Fermentek does not sell to individuals. Most of its products are marketed through major international distributors specializing in chemicals, under their own brand names. Nevertheless, Fermentek has specific impact on the biochemical market, especially in the field of mycotoxins.

Mycotoxins are toxic compounds produced by molds in human food and farm animal feeds, thus being economically important factors. Fermentek manufactures an extensive line of pure mycotoxins used as standards in food analysis. In some cases, such as Aflatoxin M2, Fermentek supplies the entire world's requirements.In 2009 Fermentek announced a product family of highly standardized calibrant solutions of main mycotoxins. These are marketed under the brand name FermaSol. In 2010 it obtained ISO 13485 accreditation in connection with the production of starting materials for experimental drug production, and with manufacturing of reference standards of food contaminants.

None of Fermentek's products have been invented by it. Fermentek's aim is to make known compounds affordable to the scientific community.

Fermentek was founded by Dr Yosef Behrend in 1994. It moved in 2004 to its new building, quadrupling its working space and greatly enlarging its manufacturing capacities.

LY294002

LY294002 is a morpholine-containing chemical compound that is a potent inhibitor of numerous proteins, and a strong inhibitor of phosphoinositide 3-kinases (PI3Ks). It is generally considered a non-selective research tool, and should not be used for experiments aiming to target PI3K uniquely.Two of these are the proto-oncogene serine/threonine-protein kinase (PIM1) and the phosphatidylinositol-4,5-bisphosphate 3-kinase P110 gamma|catalytic subunit gamma isoform. With an IC50 of 1.4 µM it is somewhat less potent than wortmannin, another well-known PI3 kinase inhibitor. However, LY294002 is a reversible inhibitor of PI3K whereas wortmannin acts irreversibly.Application of LY294002 causes a substantial acceleration of MEPP frequency (150 μM) at the frog neuromuscular junction through a mechanism that is independent of intraterminal calcium. LY294002 causes the release of MEPPs through a perturbation of synaptotagmin function.LY294002 is also a BET inhibitor (e.g. of BRD2, BRD3, and BRD4).

List of biomolecules

This is a list of articles that describe particular biomolecules or types of biomolecules.

MAP2K2

Dual specificity mitogen-activated protein kinase kinase 2 is an enzyme that in humans is encoded by the MAP2K2 gene. It is more commonly known as MEK2, but has many alternative names including CFC4, MKK2, MAPKK2 and PRKMK2.

P110α

The phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (the HUGO-approved official symbol = PIK3CA; HGNC ID, HGNC:8975), also called p110α protein, is a class I PI 3-kinase catalytic subunit. The human p110α protein is encoded by the PIK3CA gene.Its role was uncovered by molecular pathological epidemiology (MPE).

PI4KB

Phosphatidylinositol 4-kinase beta is an enzyme that in humans is encoded by the PI4KB gene.

PIK3C2A

Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing alpha polypeptide is an enzyme that in humans is encoded by the PIK3C2A gene.The protein encoded by this gene belongs to the phosphoinositide 3-kinase (PI3K) family. PI3-kinases play roles in signaling pathways involved in cell proliferation, oncogenic transformation, cell survival, cell migration, and intracellular protein trafficking. This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of Class II PI 3-kinases. C2 domains act as calcium-dependent phospholipid binding motifs that mediate translocation of proteins to membranes, and may also mediate protein-protein interactions. The PI3-kinase activity of this protein is not sensitive to nanomolar levels of the inhibitor wortmannin. This protein was shown to be able to be activated by insulin and may be involved in integrin-dependent signaling.

PIK3C2B

Phosphatidylinositol-4-phosphate 3-kinase C2 domain-containing beta polypeptide is an enzyme that in humans is encoded by the PIK3C2B gene.

PIK3CG

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform is an enzyme that in humans is encoded by the PIK3CG gene.

Penicillium proteolyticum

Penicillium proteolyticum is an anamorph species of fungus in the genus Penicillium which produces wortmannin.

Phosphoinositide 3-kinase

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (PtdIns). The pathway, with oncogene PIK3CA and tumor suppressor PTEN, is implicated in the sensitivity of cancer tumors to insulin and IGF1, and in calorie restriction.

Phosphoinositide 3-kinase inhibitor

A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class of medical drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signalling pathway for many cellular functions such as growth control, metabolism and translation initiation. Within this pathway there are many components, inhibition of which may result in tumor suppression. These anti-cancer drugs are examples of targeted therapy.There are a number of different classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha, p110 beta, p110 gamma and p110 delta. The inhibitors being studied inhibit one or more isoforms of the class I PI3Ks.They are being actively investigated for treatment of various cancers.They are also being considered for inflammatory respiratory disease.

Platelet-derived growth factor

Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).

PDGF is a potent mitogen for cells of mesenchymal origin, including fibroblasts, smooth muscle cells and glial cells. In both mouse and human, the PDGF signalling network consists of five ligands, PDGF-AA through -DD (including -AB), and two receptors, PDGFRalpha and PDGFRbeta. All PDGFs function as secreted, disulphide-linked homodimers, but only PDGFA and B can form functional heterodimers.

Though PDGF is synthesized, stored (in the alpha granules of platelets), and released by platelets upon activation, it is also produced by other cells including smooth muscle cells, activated macrophages, and endothelial cellsRecombinant PDGF is used in medicine to help heal chronic ulcers and in orthopedic surgery and periodontics as an alternative to bone autograft to stimulate bone regeneration and repair.

Receptor-mediated endocytosis

Receptor-mediated endocytosis (RME), also called clathrin-mediated endocytosis, is a process by which cells absorb metabolites, hormones, proteins – and in some cases viruses – by the inward budding of the plasma membrane (invagination). This process forms vesicles containing the absorbed substances and is strictly mediated by receptors on the surface of the cell. Only the receptor-specific substances can enter the cell through this process.

Roger L. Williams

Roger Lee Williams is a structural biologist and group leader at the Medical Research Council (MRC) Laboratory of Molecular Biology. His group studies the form and flexibility of protein complexes that associate with and modify lipid cell membranes. His work concerns the biochemistry, structures and dynamics of these key enzyme complexes.

Viridin

Viridin is an antifungal metabolite of Gliocladium virens that was first reported in 1945. Belonging to a class of molecules known as furanosteroids, it has a characteristic highly strained electrophilic furan ring fused between C-4 and C-6 of the steroid framework. Members of this family, including wortmannin, are known to be potent, irreversible covalent inhibitors of phosphoinositide 3-kinases (PI3Ks).

5-HT1
5-HT2
5-HT37

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