Wortmannin, a steroid metabolite of the fungi '' Penicillium funiculosum'', ''

Talaromyces wortmannii ''Talaromyces'' is a genus of fungi in the family Trichocomaceae. Described in 1955 by American mycologist Chester Ray Benjamin, species in the genus form soft, cottony fruit bodies (ascocarps) with cell walls made of tightly interwoven hyphae. ...

'', is a non-specific,

covalent A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

inhibitor of

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 i ...

s (PI3Ks). It has an ''in vitro'' inhibitory concentration (''IC''₅₀) of around 5 nM, making it a more potent inhibitor than

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 ...

, another commonly used

PI3K inhibitor Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI ...

. It displays a similar potency ''in vitro'' for the class I, II, and

III III or iii may refer to: Companies * Information International, Inc., a computer technology company * Innovative Interfaces, Inc., a library-software company * 3i, formerly Investors in Industry, a British investment company Other uses * Ins ...

PI3K members although it can also inhibit other PI3K-related enzymes such as

mTOR The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MT ...

, DNA-PKcs, some

phosphatidylinositol 4-kinase In enzymology, a 1-phosphatidylinositol 4-kinase () is an enzyme that catalyzes the chemical reaction :ATP + 1-phosphatidyl-1D-myo-inositol \rightleftharpoons ADP + 1-phosphatidyl-1D-myo-inositol 4-phosphate Thus, the two substrates of this enzy ...

myosin light chain kinase Myosin light-chain kinase also known as MYLK or MLCK is a serine/threonine-specific protein kinase that phosphorylates a specific myosin light chain, namely, the regulatory light chain of myosin II. General structural features While there ar ...

(MLCK) and

mitogen-activated protein kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...

(MAPK) at high concentrations Wortmannin has also been reported to inhibit members of the

polo-like kinase Polo-like kinases (Plks) are regulatory serine/threonin kinases of the cell cycle involved in mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis.Barr, Francis A., Herman HW Silljé, and Erich A. Nigg. "Polo-like kinases and the ...

family with ''IC''₅₀ in the same range as for PI3K. 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 Cell biology (also cellular biology or cytology) is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and ...

reagent that has been used previously in research to inhibit

DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...

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). Thi ...

and cell proliferation.

Phosphoinositide-3-kinase

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 i ...

(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

; as such, it has detrimental influence on memory and impairs spatial learning abilities.

Derivatives

Medicinal chemistry research has been conducted to identify wortmannin

derivatives The derivative of a function is the rate of change of the function's output relative to its input value. Derivative may also refer to: In mathematics and economics * Brzozowski derivative in the theory of formal languages * Formal derivative, an ...

that are more stable, while not losing its therapeutic effect.

Sonolisib

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

irreversible inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...

of PI-3 kinase with efficacy when delivered orally. Sonolisib was put in a phase 1 clinical trial by Oncothyreon.PX-866 June 2010
/ref> The clinical development plan for sonolisib includes both standalone and combination therapy in major human cancers. In 2010, sonolisib was starting 4 phase II trials for solid tumors. The company gave an update on its phase 2 trials in Jun 2012. Phase 1 results (with docetaxel) published Aug 2013. 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". In Sept 2015 as Phase 2 trial for recurrent

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ch ...

reported not meeting its primary endpoint.

References

External links

Wortmannin bound to proteins
in the PDB {{Serotonin antagonists Acetate esters Furans Delta-lactones Phosphoinositide 3-kinase inhibitors Covalent inhibitors