677331-12-3

Usage

Uses

Used in Pharmaceutical Industry:
iCRT 14 is used as a potent inhibitor for Wnt/β-catenin-mediated cell signaling studies, which is crucial for understanding the molecular mechanisms of various diseases and developing targeted therapies.
Used in Cancer Research:
iCRT 14 is used as a research tool to induce marked G0/G1 cell cycle arrest in HCT-116 and HT29 cell lines, providing valuable insights into the regulation of cell cycle progression and potential therapeutic applications in cancer treatment.
Used in Drug Development:
iCRT 14 is used as a lead compound in the development of novel drugs targeting the Wnt/β-catenin signaling pathway, which plays a critical role in various diseases, including cancer, and holds promise for the discovery of new therapeutic agents.

Biological Activity

iCRT14 is a β-catenin/Tcf inhibitor with a Ki value of 54 ± 5.2 μM in the HFP assay.

Biochem/physiol Actions

iCRT14 belongs to the thiazolidinedione class of β-catenin-responsive transcription inhibitors. It decreases the levels of Dishevelled protein and modulates the binding of T-cell factor (TCF) to DNA. It results in consistent decrease in reduction of cell proliferation and tumor growth in colon cancer cells.

in vitro

iCRT14 inhibits the transcriptional activity of canonical Wnt signaling, downregulates Wnt/β-catenin-induced target genes, and inhibits the growth of colorectal cancer cells in vivo. iCRT14 moderately reduced Dvl without affecting Dvl phosphorylation. In mammalian HEK293 cells, iCRT14 inhibits the Wnt response element STF16-luc reporter gene with IC50 of 40.3 nM. In addition to affecting the TCF-β-catenin interaction, iCRT14 also interferes with the binding of TCF to DNA.

in vivo

In HCT116 and HT29 xenograft models, iCRT14 caused a significant decrease in CycD1 and decreased tumor proliferation. In addition, the initial tumor growth rate decreased significantly during the first three weeks of dosing. After 19 days of administration, the tumor growth rate returned to the control level. During the study, the mice did not show any symptoms of systemic toxic effects or weight loss. The modified compound can be rapidly metabolized in the body, and its bioavailability is low.

references

[1] gonsalves f c, klein k, carson b b, et al. an rnai-based chemical genetic screen identifies three small-molecule inhibitors of the wnt/wingless signaling pathway. proceedings of the national academy of sciences, 2011, 108(15): 5954-5963.