Wortmannin

PI3K/AKT pathway inhibitor; Inhibits PI3K and PLKs

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PI3K/AKT pathway inhibitor; Inhibits PI3K and PLKs
From: 69 USD

Overview

Wortmannin is a fungal metabolite that covalently binds to and inhibits phosphatidylinositol-3-kinases (PI3K) of class I, II, and III. Species-specific differences in the class II PI3Ks determine sensitivity with IC₅₀ = 5, 50, and 450 nM for Drosophila, mouse, and human, respectively (Fruman et al.; Wymann et al.; Okada et al.). Wortmannin also inhibits polo-like kinases (PLK) PLK1 and PLK3 with IC₅₀ = 24 and 49 nM, respectively (Liu et al. 2005; Liu et al. 2007). At high concentrations it can also inhibit other kinases such as mammalian target of rapamycin (mTOR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), phosphatidylinositol-4-kinase (PI4K), myosin light-chain kinase (MLCK), and mitogen-activated protein kinase (MAPK; Fruman et al.; Meyers & Cantley; Hartley et al.; Brunn et al.; Nakanishi et al.).

CANCER RESEARCH
· Exhibits cytotoxic activity on a number of human tumor cell lines in vitro, and anti-tumor activity in mouse xenografts of C3H mammary carcinoma and BxPC-3 pancreatic carcinoma cells (Schultz et al.; Yuan et al.).
Alternative Names:
KY 12420
CAS Number:
19545-26-7
Chemical Formula:
C₂₃H₂₄O₈
Molecular Weight:
428.4 g/mol
Purity:
≥ 98%
Pathway:
PI3K/AKT; PLK
Target:
PI3K; PLK

Scientific Resources

Product Documentation

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Educational Materials

(3)

Data and Publications

Publications

(11)
The Journal of biological chemistry 2007

Polo-like kinases inhibited by wortmannin. Labeling site and downstream effects.

Liu Y et al.

Abstract

Polo-like kinases play crucial roles throughout mitosis. We previously reported that wortmannin potently inhibits Polo-like kinase 1 (Plk1). In this study, we show that wortmannin also strongly inhibits Polo-like kinase 3 (Plk3). To further characterize this inhibition, we identified the sites of labeling on Plk1 and Plk3 targeted by AX7503, a tetramethylrhodamine-wortmannin conjugate. AX7503 labeling on Plk1 and Plk3 was found to occur on a conserved ATP binding site residue. In addition, we show that wortmannin inhibits Plk3 activity in live cells at concentrations commonly used to inhibit the more well known targets of wortmannin, the phosphoinositide 3-kinases. Importantly, we found that inhibition of Plk3 by wortmannin lead to a decrease in phosphorylation of p53 on serine 20 induced by DNA damage, demonstrating the effect of wortmannin on a downstream Plk3 target. Taken together, our results suggest that wortmannin can affect multiple functions of Plk3 in cell cycle progression and at the DNA damage check point. The identification of the labeling sites of Plk1 and Plk3 by AX7503 may be useful in designing more effective compounds to target Polo-like kinases for cancer treatment and also may be useful for the structural study of Plk domains.
Chemistry & biology 2007

Covalent reactions of wortmannin under physiological conditions.

Yuan H et al.

Abstract

Wortmannin (Wm), a steroid-like molecule of 428.4 Da, appears to be unstable in biological fluids (apparent chemical instability), yet it exhibits an antiproliferative activity in assays employing a 48 hr incubation period (prolonged bioactivity), a situation we refer to as the wortmannin paradox." Under physiological conditions�
Chemistry & biology 2005

Wortmannin, a widely used phosphoinositide 3-kinase inhibitor, also potently inhibits mammalian polo-like kinase.

Liu Y et al.

Abstract

Polo-like kinases (PLKs) play critical roles throughout mitosis. Here, we report that wortmannin, which was previously thought to be a highly selective inhibitor of phosphoinositide (PI) 3-kinases, is a potent inhibitor of mammalian PLK1. Observation of the wortmannin-PLK1 interaction was enabled by a tetramethylrhodamine-wortmannin conjugate (AX7503) that permits rapid detection of PLK1 activity and expression in complex proteomes. Importantly, we show that wortmannin inhibits PLK1 activity in an in vitro kinase assay with an IC(50) of 24 nM and when incubated with intact cells. Taken together, our results indicate that, at the concentrations of wortmannin commonly used to inhibit PI 3-kinases, PLK1 is also significantly inhibited.
Annual review of biochemistry 1998

Phosphoinositide kinases.

Fruman DA et al.

Abstract

Phosphatidylinositol, a component of eukaryotic cell membranes, is unique among phospholipids in that its head group can be phosphorylated at multiple free hydroxyls. Several phosphorylated derivatives of phosphatidylinositol, collectively termed phosphoinositides, have been identified in eukaryotic cells from yeast to mammals. Phosphoinositides are involved in the regulation of diverse cellular processes, including proliferation, survival, cytoskeletal organization, vesicle trafficking, glucose transport, and platelet function. The enzymes that phosphorylate phosphatidylinositol and its derivatives are termed phosphoinositide kinases. Recent advances have challenged previous hypotheses about the substrate selectivity of different phosphoinositide kinase families. Here we re-examine the pathways of phosphoinositide synthesis and the enzymes involved.
The Journal of biological chemistry 1997

Cloning and characterization of a wortmannin-sensitive human phosphatidylinositol 4-kinase.

Meyers R and Cantley LC

Abstract

Phosphatidylinositol (PtdIns) 4-kinases catalyze the synthesis of PtdIns-4-P, the immediate precursor of PtdIns-4,5-P2. Here we report the cloning of a novel, ubiquitously expressed PtdIns 4-kinase (PI4Kbeta). The 2.4-kilobase pair cDNA encodes a putative translation product of 801 amino acids which shows greatest homology to the yeast PIK1 gene. The recombinant protein exhibits lipid kinase activity when expressed in Escherichia coli, and specific antibodies recognize a 110-kDa PtdIns 4-kinase in cell lysates. The biochemical properties of PI4Kbeta are characteristic of a type III enzyme. Interestingly, both recombinant PI4Kbeta and the endogenous protein are inhibited by 150 nM wortmannin, suggesting that we have cloned the previously described PtdIns 4-kinase that is responsible for regulating the synthesis of agonist-sensitive pools of polyphosphoinositides (Nakanishi, S., Catt, J. K., and Balla, T. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 5317-5321).
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