Delivery of the Porcupine Inhibitor WNT974 in Mice

Zhang, Li Shu; Lum, Lawrence

doi:10.1007/978-1-4939-6393-5_12

Cited by 18 publications

(15 citation statements)

References 11 publications

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“…16b ). To determine whether inhibition of the Wnt signaling pathway could ameliorate the observed fibrosis, we utilized LGK974, a small molecule inhibitor of all secreted Wnts 39 . Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Diabetes was induced in 10-week-old male mice with five consecutive IP doses of STZ 50 mg/kg in 10 mmol/L citrate buffer (pH 4.5). Wnt inhibitor (LGK974) was provided to 16-week-STZ-treated diabetic mice using a dose of 5 mg/kg at a frequency of six doses per week for 8 weeks 39 . Etomoxir (20 mg/kg) and C75 (15 mg/kg) were dosed (IP) three times per week for 3 weeks in GR ECKO and control littermates.…”

Section: Methodsmentioning

confidence: 99%

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Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

et al. 2021

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Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

et al. 2021

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“…C57BL/6 mice [12-wk-old (LAD studies) or 3-to 12-mo-old (other studies)] were used. Wnt-974 (Active Biochem) was prepared in 0.5% (wt/vol) methylcellulose (Sigma)/0.5% (vol/vol) Tween-80 (Sigma) and administered by oral gavage at 5 mg/kg per mouse once per day for indicated time periods, as previously described (47). All animal experiments were performed in accordance to regulatory standards as accepted by the Institutional Animal Care and Use Committee at the University of Texas Southwestern Medical Center.…”

Section: Methodsmentioning

confidence: 99%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

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“…These results indicate that CDs and LGK974 effectively form supramolecular complexes. These complexes are soluble in water and could be an alternative to the standard preparation for oral gavage, which requires surfactants and sonication to produce a suspension that remains insoluble [9,11,27,28].…”

Section: Resultsmentioning

confidence: 99%

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Guimarães

Tan

Tammela

et al. 2018

Journal of Controlled Release

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Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D 1H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allografts in mice. Further, CD:LGK974 complexes increased the bioavailability upon oral administration in mice compared to free LGK974. In a mouse lung cancer allograft model, CD:LGK974 complexes induced potent Wnt signaling inhibition with reduced intestinal toxicity compared to treatment with free drug. Collectively, the development of these complexes enables safer and repeated oral or parenteral administration of Wnt signaling inhibitors, which hold promise for the treatment of multiple types of malignancies.

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Delivery of the Porcupine Inhibitor WNT974 in Mice

Cited by 18 publications

References 11 publications

Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

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