Modulation of Wnt Signaling Through Inhibition of Secreted Frizzled-Related Protein I (sFRP-1) with N-Substituted Piperidinyl Diphenylsulfonyl Sulfonamides

Moore, William; Kern, Jeffrey C.; Bhat, Ramesh A.; Commons, Thomas J.; Fukayama, Shoichi; Goljer, Igor; Krishnamurthy, Girija; Magolda, Ronald L.; Nogle, Lisa; Pitts, Keith; Stauffer, Barb; Trybulski, Eugene J.; Welmaker, Gregory S.; Wilson, Matthew A.; Bodine, Peter V.N.

doi:10.1021/jm801144h

Cited by 48 publications

(35 citation statements)

References 24 publications

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“…To improve the compound effect in the Wnt signaling as well as to identify the structure region modulating Wnt/sFRP1 binding, the authors performed structure-activity relationship in the sulfone portion. As result, they found isosteric derivatives that improved binding and potency of this molecule on Wnt signaling (Moore et al, 2009(Moore et al, , 2010. This strategy points toward a promising future in the study of small molecules, such as flavonoids, with biological potential.…”

Section: Resultsmentioning

confidence: 90%

“…More importantly, modifications on these structures may shed light in the mechanisms by which flavonoids impair cancer growth. A good chemical strategy was the recent discovery of the N-substitution of the diphenylsulfonyl sulfonamide 1 (Moore et al, 2009(Moore et al, , 2010. This piperidinyl was identified as an inhibitor of sFRP1 (secreted FrizzledRelated Protein1) binding to Wnt ligands, therefore promoting Wnt signaling.…”

Section: Resultsmentioning

confidence: 99%

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Flavonoids: Potential Wnt/beta-catenin signaling modulators in cancer

et al. 2011

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Flavonoids are polyphenolic compounds found throughout the plant kingdom. They occur in every organ but are usually concentrated in leaves and flowers. During the last two decades, in vitro and in vivo studies demonstrated that flavonoids have inhibitory effects on human diseases through targeting of multiple cellular signaling components. Wnt/β-catenin signaling regulates proliferation, differentiation and fate specification in developmental stages and controls tissue homeostasis in adult life. For these reasons, this pathway has received great attention in the last years as potential pathway involved in distinct Human pathologies. In this review we discuss the emerging potential mechanisms for flavonoids on Wnt/β-catenin signaling in cancer and possible investigation strategies to understand flavonoids mode of action on this signaling pathway.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Flavonoids: Potential Wnt/beta-catenin signaling modulators in cancer

et al. 2011

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“…Moore et al 2009Moore et al , 2010] (see Figure 2 and Table 1). No study has explicitly studied the in vivo osteogenic activity of SFRP antibodies or inhibitors.…”

Section: Deoxycholic Acidmentioning

confidence: 99%

Wnt signaling in bone formation and its therapeutic potential for bone diseases

Kim

Liu

Wang

et al. 2013

Therapeutic Advances in Musculoskeletal

284

239

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Abstract:The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.

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“…Two classes of molecules have been so far tested. The first is a diphenylsulfone sulphonamide, which binds specifically to Sfrp1, suppresses osteocyte apoptosis and stimulates ex vivo murine bone formation in an organ culture assay Moore et al 2009). The second one is a minooxothiazolidine, which also binds to Sfrp1.…”

Section: Sfrp1 Prevents Bone Repairmentioning

confidence: 99%