Kenpaullone

WNT pathway activator; Inhibits GSK3ß

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Kenpaullone

WNT pathway activator; Inhibits GSK3

10 mg
Catalog #72782
202 USD

Overview

Kenpaullone is an ATP-competitive inhibitor of glycogen synthase kinase 3β (GSK-3β; Bain et al.; Leclerc et al.; Zaharevitz et al.). It inhibits GSK-3β, Cdk1/cyclin B, Cdk2/cyclin A, Cdk5/p25, and lymphocyte kinase with IC₅₀ values of 0.23, 0.4, 0.68, 0.85, and 0.47 µM, respectively (Bain et al.; Zaharevitz et al.).

REPROGRAMMING
· Replaces Klf4 in the generation of induced pluripotent stem (iPS) cells from mouse embryonic fibroblasts (MEFs) transduced with Oct4, Sox2, and c-Myc (Lyssiotis et al.).

DIFFERENTIATION
· Enhances neuronal differentiation in rat and human neural precursor cell cultures (Castelo-Branco et al.; Lange et al.).
· Promotes survival of motor neurons derived from mouse embryonic stem (ES) cells and from Amyotrophic Lateral Sclerosis (ALS) patient iPS cells (Yang et al.).

CANCER RESEARCH
· Inhibits KLF4 expression and self-renewal in breast cancer stem cells in vitro (Yu et al.).
Alternative Names:
9-Bromopaullone; NSC 664704
CAS Number:
142273-20-9
Chemical Formula:
C₁₆H₁₁BrN₂O
Molecular Weight:
327.2 g/mol
Purity:
≥ 98%
Pathway:
WNT
Target:
GSK3

Scientific Resources

Product Documentation

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Educational Materials

(4)

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This product is designed for use in the following research area(s) as part of the highlighted workflow stage(s). Explore these workflows to learn more about the other products we offer to support each research area.

Data and Publications

Publications

(8)
Cell stem cell 2013 JUN

A small molecule screen in stem-cell-derived motor neurons identifies a kinase inhibitor as a candidate therapeutic for ALS.

Yang YM et al.

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease, characterized by motor neuron (MN) death, for which there are no truly effective treatments. Here, we describe a new small molecule survival screen carried out using MNs from both wild-type and mutant SOD1 mouse embryonic stem cells. Among the hits we found, kenpaullone had a particularly impressive ability to prolong the healthy survival of both types of MNs that can be attributed to its dual inhibition of GSK-3 and HGK kinases. Furthermore, kenpaullone also strongly improved the survival of human MNs derived from ALS-patient-induced pluripotent stem cells and was more active than either of two compounds, olesoxime and dexpramipexole, that recently failed in ALS clinical trials. Our studies demonstrate the value of a stem cell approach to drug discovery and point to a new paradigm for identification and preclinical testing of future ALS therapeutics.
Oncogene 2011 MAY

Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion.

Yu F et al.

Abstract

Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1, side population and by in vitro mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation in vitro and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell-like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer.
Neuroscience letters 2011 JAN

Small molecule GSK-3 inhibitors increase neurogenesis of human neural progenitor cells.

Lange C et al.

Abstract

Human neural progenitor cells provide a source for cell replacement therapy to treat neurodegenerative diseases. Therefore, there is great interest in mechanisms and tools to direct the fate of multipotent progenitor cells during their differentiation to increase the yield of a desired cell type. We tested small molecule inhibitors of glycogen synthase kinase-3 (GSK-3) for their functionality and their influence on neurogenesis using the human neural progenitor cell line ReNcell VM. Here we report the enhancement of neurogenesis of human neural progenitor cells by treatment with GSK-3 inhibitors. We tested different small molecule inhibitors of GSK-3 i.e. LiCl, sodium-valproate, kenpaullone, indirubin-3-monoxime and SB-216763 for their ability to inhibit GSK-3 in human neural progenitor cells. The highest in situ GSK-3 inhibitory effect of the drugs was found for kenpaullone and SB-216763. Accordingly, kenpaullone and SB-216763 were the only drugs tested in this study to stimulate the Wnt/β-catenin pathway that is antagonized by GSK-3. Analysis of human neural progenitor differentiation revealed an augmentation of neurogenesis by SB-216763 and kenpaullone, without changing cell cycle exit or cell survival. Small molecule inhibitors of GSK-3 enhance neurogenesis of human neural progenitor cells and may be used to direct the differentiation of neural stem and progenitor cells in therapeutic applications.
Proceedings of the National Academy of Sciences of the United States of America 2009 JUN

Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4.

Lyssiotis CA et al.

Abstract

Ectopic expression of defined transcription factors can reprogram somatic cells to induced pluripotent stem (iPS) cells, but the utility of iPS cells is hampered by the use of viral delivery systems. Small molecules offer an alternative to replace virally transduced transcription factors with chemical signaling cues responsible for reprogramming. In this report we describe a small-molecule screening platform applied to identify compounds that functionally replace the reprogramming factor Klf4. A series of small-molecule scaffolds were identified that activate Nanog expression in mouse fibroblasts transduced with a subset of reprogramming factors lacking Klf4. Application of one such molecule, kenpaullone, in lieu of Klf4 gave rise to iPS cells that are indistinguishable from murine embryonic stem cells. This experimental platform can be used to screen large chemical libraries in search of novel compounds to replace the reprogramming factors that induce pluripotency. Ultimately, such compounds may provide mechanistic insight into the reprogramming process.
Journal of cell science 2004 NOV

GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons.

Castelo-Branco G et al.

Abstract

Wnts are important regulators of dopamine (DA) neuron differentiation in the developing ventral mesencephalon and could thus serve as potential tools in the treatment of Parkinson's disease. In this study, we investigate whether established intracellular Wnt signalling components could modulate the development of DA neurons. Two chemical inhibitors of glycogen synthase kinase (GSK)-3beta, indirubin-3-monoxime and kenpaullone, were found to increase neuronal differentiation in ventral mesencephalon precursor cultures. In addition, the GSK-3beta-specific inhibitor kenpaullone increased the size of the DA neuron population through conversion of precursors expressing the orphan nuclear receptor-related factor 1 into tyrosine hydroxylase positive neurons, thereby mimicking an effect of Wnts. We show that GSK-3beta inhibitors stabilized beta-catenin and that overexpression of beta-catenin in ventral mesencephalic precursors resulted in increased DA differentiation. The three- to fivefold increase in DA differentiation of precursor cells by GSK-3beta inhibitors suggests that such compounds could be used to improve stem/precursor cell therapy approaches in Parkinson's disease.
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