Sulfonamide Inhibitors of β-Catenin Signaling as Anticancer Agents with Different Output on c-MYC

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• The Wnt/β-catenin signaling pathway is frequently deregulated in various cancers.
• Aberrant nuclear accumulation of β-catenin drives tumorigenesis.
• There is a clinical need for approved drugs targeting this pathway.

Purpose of the Study:

• To identify and characterize novel inhibitors of the Wnt/β-catenin pathway.
• To evaluate the therapeutic potential of identified compounds as anticancer agents.

Main Methods:

• In vitro Wnt reporter assays to determine inhibitory concentration (IC50).
• Assessment of c-MYC protein levels.
• Cell viability assays using HCT116 colon cancer cells.
• In silico drug-likeness evaluation (Lipinski and Veber rules).
• Prediction of cell permeability (Caco-2 and MDCK models).

Main Results:

• Ethyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)benzoate (compound 14) inhibited Wnt reporter activity with an IC50 of 7.0 μM.
• Compound 14 significantly reduced c-MYC levels.
• It inhibited HCT116 colon cancer cell growth with an IC50 of 20.2 μM.
• Compound 14 adhered to Lipinski and Veber rules and predicted high cell permeability (Papp >500 nm/s).

Conclusions:

• Compound 14 demonstrates potent inhibition of Wnt/β-catenin signaling.
• Its favorable drug-like properties and demonstrated anticancer activity suggest potential for novel therapeutic development.