Wortmannin
Encyclopedia
Wortmannin, a furanosteroid metabolite of the fungi Penicillium funiculosum
, Talaromyces (Penicillium) wortmannii,
is a specific, covalent inhibitor of phosphoinositide 3-kinase
s (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-PK, some phosphatidylinositol 4-kinases, myosin light chain kinase (MLCK) and mitogen-activated protein kinase
(MAPK) at high concentrations , Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 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
reagent that has been used previously in research to inhibit DNA repair
, receptor-mediated endocytosis
and cell proliferation .
Wortmannin is a known and potent PI3K inhibitor; as such, it was shown to have enhancing influence on memory and impair learning abilities.
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 is currently in a phase 1 clinical trial by Oncothyreon company. The clinical development plan for PX-866 includes both standalone and combination therapy in major human cancers.
Penicillium funiculosum
Penicillium funiculosum is a plant pathogen.-External links:**...
, Talaromyces (Penicillium) wortmannii,
is a specific, covalent inhibitor of phosphoinositide 3-kinase
Phosphoinositide 3-kinase
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. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
s (PI3Ks). It has an in vitro inhibitory concentration
IC50
The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance is needed to inhibit a given biological process by half...
(IC50) of around 5 nM, making it a more potent inhibitor than LY294002
LY294002
LY294002 is a morpholine derivative of quercetin. It is a potent inhibitor of phosphoinositide 3-kinases . Two of these are the proto-oncogene serine/threonine-protein kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform...
, another commonly used PI3K inhibitor. It displays a similar potency in vitro for the class I
Class I PI 3-kinases
Class I PI 3-kinases are a subgroup of the enzyme family, phosphoinositide 3-kinase that possess a common protein domain structure, substrate specificity, and method of activation...
, II
Class II PI 3-kinases
Class II PI 3-kinases are a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation....
, and III PI3K members although it can also inhibit other PI3K-related enzymes such as mTOR, DNA-PK, some phosphatidylinositol 4-kinases, myosin light chain kinase (MLCK) and mitogen-activated protein kinase
Mitogen-activated protein kinase
Mitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
(MAPK) at high concentrations , Wortmannin has also been reported to inhibit members of the polo-like kinase family with IC50 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
Cell biology is a scientific discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level...
reagent that has been used previously in research to inhibit DNA repair
DNA repair
DNA repair refers to 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 UV light and radiation can cause DNA damage, resulting in as many as 1...
, receptor-mediated endocytosis
Receptor-mediated endocytosis
Receptor-mediated endocytosis , also called clathrin-dependent endocytosis, is a process by which cells internalize molecules by the inward budding of plasma membrane vesicles containing proteins with receptor sites specific to the molecules being internalized.-Process:After the binding of a...
and cell proliferation .
Background: 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 enhancing influence on memory and impair learning abilities.
Derivates
In order to stabilize the Wortmannin molecule while not losing its therapeutic effect, numerous derivates were synthesized from WortmanninOne 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 is currently in a phase 1 clinical trial by Oncothyreon company. The clinical development plan for PX-866 includes both standalone and combination therapy in major human cancers.
External links
Vendors' product pages- Wortmannin product page from FermentekFermentekFermentek Ltd. is a biotechnological company, located in Atarot industrial zone, Jerusalem, Israel, specializing 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...