Structure–activity relationship studies of small-molecule inhibitors of Wnt response

Lü, Jianming; Ma, Zhiqiang; Hsieh, Jen‐Chieh; Fan, Chih Wei; Chen, Baozhi; Longgood, Jamie; Williams, Noelle S.; Amatruda, James F.; Lum, Lawrence; Chen, Chuo

doi:10.1016/j.bmcl.2009.04.040

Cited by 128 publications

(128 citation statements)

References 11 publications

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“…While the Wnt inhibitor Dkk1 was down‐regulated, Wnt effector Tcf4 was increased by Lox inhibition (Figure S4). It has been previously demonstrated that IWR‐1‐endo, an inhibitor of Wnt pathway, induces Axin2 protein levels and promotes β‐catenin degradation by stabilizing Axin‐scaffolded destructive complexes 26. Here, we found that IWR‐1‐endo treatment decreased protein levels of β‐catenin and CHOP‐10 expression induced by Lox inhibition, while subsequently repressing osteogenesis with lower expression of Runx2 and Osterix, along with lower calcium deposition (Figure 3C,D).…”

Section: Resultsmentioning

confidence: 99%

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

Jiang

Xing

Wang

et al. 2018

J Cellular Molecular Medi

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Accelerated marrow adipogenesis has been associated with ageing and osteoporosis and is thought to be because of an imbalance between adipogenic and osteogenic differentiation of mesenchymal stem cell (MSCs). We have previously found that lysyl oxidase (Lox) inhibition disrupts BMP4‐induced adipocytic lineage commitment and differentiation of MSCs. In this study, we found that lox inhibition dramatically up‐regulates BMP4‐induced expression of CCAAT/enhancer binding protein (C/EBP) homologous protein 10 (CHOP‐10), which then promotes BMP4‐induced osteogenesis of MSCs both in vitro and in vivo. Specifically, Lox inhibition or CHOP‐10 up‐regulation activated Wnt/β‐catenin signalling to enhance BMP4‐induced osteogenesis, with pro‐adipogenic p38 MAPK and Smad signalling suppressed. Together, we demonstrate that Lox/CHOP‐10 crosstalk regulates BMP4‐induced osteogenic and adipogenic fate determination of MSCs, presenting a promising therapeutic target for osteoporosis and other bone diseases.

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Section: Resultsmentioning

confidence: 99%

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

Jiang

Xing

Wang

et al. 2018

J Cellular Molecular Medi

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“…In order to test this hypothesis, we performed in vivo treatments using cell permeable small molecule inhibitors of the Wnt/ b-catenin pathway, endo-IWR-1 25 and PNU-74654 26 . Endo-IWR-1 acts as a stabilizer of Axin, thereby stimulating the degradation of cytoplasmic b-catenin and constitutively inhibiting the Wnt/b-catenin pathway, without altering the pool of membrane tethered b-catenin 25,27 .…”

Section: Resultsmentioning

confidence: 99%

“…This molecule has been shown to reduce the amount of b-catenin and to inhibit the transcriptional response to Wnt/b-catenin signalling in developing zebrafish and Xenopus embryos and larvae 28,29 , indicating its suitability for in vivo studies. In order to confirm endo-IWR-1 phenotypes, we used PNU-74654 that prevents the interaction between b-catenin and the transcription factor TCF 26,30 . Treatment with either molecule from 33 to 55 hpf allowed us to avoid interferences with earlier global functions of b-catenin 31 , and to specifically target the period during which cell proliferation reorganizes around the ventral midline and massive neural differentiation occurs.…”

Section: Resultsmentioning

confidence: 99%

Involvement of the Wnt/β-catenin pathway in neurectoderm architecture in Platynereis dumerilii

et al. 2013

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Signalling pathways are essential for the correct development of the central nervous system (CNS) in bilaterian animals. Here we show that in the CNS of the annelid Platynereis dumerilii, neural progenitor cells (NPCs) are located close to the ventral midline and express axin, a negative regulator of the Wnt/b-catenin pathway. Using pharmacological inhibitors, we observe that Wnt/b-catenin is required for the transition between proliferating NPCs and differentiating neurons. We also show that the Rho-associated kinase (Rok) is necessary for neurectoderm morphogenesis and ventral midline formation, and indirectly affects the distribution of the NPCs and the development of axonal scaffolds. Moreover, seven genes belonging to the planar cell polarity (PCP) pathway are expressed in the developing Platynereis neurectoderm, suggesting an involvement in its morphogenesis. When compared with previous studies in vertebrates, our data suggest that the involvement of the Wnt/b-catenin pathway in the control of neural cell proliferation/differentiation is ancestral to bilaterians.

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“…We used the Porcn inhibitor Wnt-C59 (C59) to reveal the role of Wnt secretion in the formation of distinct intra-and extracellular fractions of Wnt3EGFP. In parallel, IWR-1, another inhibitor of Wnt signaling acting at the level of β-catenin activity in target cells, and thus not influencing secretion, was used for in vivo comparison of inhibitor action Lu et al, 2009).…”

Section: Block Of Porcupine Affects Wnt3egfp Secretionmentioning

confidence: 99%

Modulating expression level of secreted Wnt3 influences cerebellum development in zebrafish transgenics

et al. 2015

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The boundaries of brain regions are associated with the tissuespecific secretion of ligands from different signaling pathways. The dynamics of these ligands in vivo and the impact of its disruption remain largely unknown. Using light and fluorescence microscopy for the overall imaging of the specimen and fluorescence correlation spectroscopy (FCS) to determine Wnt3 dynamics, we demonstrated that Wnt3 regulates cerebellum development during embryogenesis using zebrafish wnt3 transgenics with either tissue-specific expression of an EGFP reporter or a functionally active fusion protein, Wnt3EGFP. The results suggest a state of dynamic equilibrium of Wnt3EGFP mobility in polarized neuroepithelial-like progenitors in the dorsal midline and cerebellar progenitors on the lateral side. Wnt3EGFP is secreted from the cerebellum as shown by measurements of its mobility in the ventricular cavity. The importance of Wnt secretion in brain patterning was validated with the Porcn inhibitor Wnt-C59 (C59), which, when applied early, reduced membrane-bound and secreted fractions of Wnt3EGFP and led to a malformed brain characterized by the absence of epithalamus, optic tectum and cerebellum. Likewise, interference with Wnt secretion later on during cerebellar development negatively impacted cerebellar growth and patterning. Our work, supported by quantitative analysis of protein dynamics in vivo, highlights the importance of membrane-localized and secreted Wnt3 during cerebellum development.

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Structure–activity relationship studies of small-molecule inhibitors of Wnt response

Cited by 128 publications

References 11 publications

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

A Lox/CHOP‐10 crosstalk governs osteogenic and adipogenic cell fate by MSCs

Involvement of the Wnt/β-catenin pathway in neurectoderm architecture in Platynereis dumerilii

Modulating expression level of secreted Wnt3 influences cerebellum development in zebrafish transgenics

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