Identification of iminooxothiazolidines as secreted frizzled related protein-1 inhibitors

Shi, Mengxiao; Stauffer, Barbara; Bhat, Ramesh A.; Billiard, Julia; Ponce-de-Leon, Helga; Seestaller-Wehr, Laura; Fukayama, Shoichi; Mangine, Annamarie; Moran, Robert A.; Krishnamurthy, Girija; Bodine, Peter V.N.; Gopalsamy, Ariamala

doi:10.1016/j.bmcl.2009.09.085

Cited by 12 publications

(15 citation statements)

References 16 publications

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“…sFRP manipulations can also regulate WNT signaling. Iminooxothiazolidines (compound 1–34) are reported to be potential inhibitors of SFRP1 and to promote osteogenesis ( Shi et al, 2009 ). Following a detailed screening of approximately 440,000 compounds, Bodine et al (2009) also described an inhibitor of sFRP1 called WAY-316606 that led to increased bone formation; the same group proposed the use of several other similar inhibitory compounds ( Moore et al, 2010 ).…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

WNT Signaling in Cardiac and Vascular Disease

et al. 2017

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WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-β and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.

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Section: Therapeutic Interventionsmentioning

confidence: 99%

WNT Signaling in Cardiac and Vascular Disease

et al. 2017

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“…Shi and colleagues developed imino-oxothiazolidine derivatives, and one of these showed encouraging results in ex vivo cultures of mouse calvaria. Indeed, the compound increased bone formation and the number of osteoblasts in comparison with untreated control [77].…”

Section: Sfrps As Potential Therapeutic Options?mentioning

confidence: 89%

Secreted Frizzled‐related proteins (sFRPs) in osteo‐articular diseases: much more than simple antagonists of Wnt signaling?

2019

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Osteo‐articular diseases are characterized by a dysregulation of joint and/or bone homeostasis. These include diseases affecting the joints originally, such as osteoarthritis and rheumatoid arthritis, or the bone, such as osteoporosis. Inflammation and the involvement of Wingless‐related integration site (Wnt) signaling pathways are key pathophysiological features of these diseases resulting in tissue degradation by matrix‐degrading enzymes, namely matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTs), secreted by the joint resident cells and/or by infiltrating immune cells. Activation of Wnt signaling pathways is modulated by different families of proteins, including Dickkopfs and the secreted Frizzled‐related proteins (sFRPs). The sFRP family is composed of five secreted glycoproteins in mammals that regulate Wnt signaling in the extracellular compartment. Indeed, sFRPs are able to bind both to the soluble Wnt ligands and to their cell membrane receptors, the Frizzled proteins. Their expression profile is altered in osteo‐articular diseases, suggesting that they could account for the abnormal activation of Wnt pathways. In the present article, we review how sFRPs are more than simple antagonists of the Wnt signaling pathways and discuss their pathophysiological relevance in the context of osteo‐articular diseases. We detail their Wnt‐dependent and their Wnt‐independent roles, with a particular emphasis on their ability to modulate the inflammatory response and extracellular matrix (ECM) remodeling. We also discuss their potential therapeutic use with a focus on bone remodeling, osteo‐articular cancers, and tissue engineering.

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“…Therefore, it would be optimal to develop topically applicable, nondrug SFRP1 antagonists, the long‐term application of which in cosmetic formulations is expected to limit agent toxicity. Therefore, we have explored a group of potentially cosmetically applicable imino‐oxothiazolidine derivates that are known to inhibit SFRP1 activity in vitro 3 as candidate human hair growth promoters.…”

Section: Figurementioning

confidence: 99%

“…First we evaluated the toxicological profile of selected imino‐oxothiazolidine derivates 3 using VEGA, a quantitative in silico platform that predicts a range of compound toxicity parameters. This revealed compound C1 – methyl 2‐{[2‐(2‐imino‐4‐oxo‐thiazolidin‐5‐yl)acetyl]amino}‐4,5‐dimethylthiophene‐3‐carboxylate 3 – to be the most favourable derivate due to the lack of toxicological alerts. C1 was next assessed for its safety in dermatological applications.…”

Section: Figurementioning

confidence: 99%

“…Collectively, we unveil a new cosmeceutically applicable SFRP1 antagonist, the Wnt‐activating imino‐oxothiazolidine derivate, C1, 3 which prolongs anagen and stimulates HMK proliferation ex vivo . Given the favourable toxicological profile of C1, its topical application therefore deserves to be clinically explored as an adjuvant cosmetic therapy for hair loss disorders associated with premature catagen development leading to telogen effluvium, such androgenetic alopecia 8 …”

Section: Figurementioning

confidence: 99%

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