1. Sulfonamide inhibitors of beta-catenin signaling as anticancer agents with different output on c-Myc
- Author
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Alessia Ciogli, Laura Di Magno, Romano Silvestri, Fiorella Di Pastena, Antonio Coluccia, Giuseppe La Regina, Simone Manetto, Marianna Nalli, Marella Maroder, Michela Puxeddu, and Gianluca Canettieri
- Subjects
Colorectal cancer ,Antineoplastic Agents ,anticancer ,01 natural sciences ,Biochemistry ,Proto-Oncogene Proteins c-myc ,chemistry.chemical_compound ,Drug Discovery ,sulfonamide ,beta-catenin ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,IC50 ,Wnt Signaling Pathway ,beta Catenin ,Cell Proliferation ,Pharmacology ,Sulfonamides ,Trifluoromethyl ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Sulfonamide (medicine) ,Wnt signaling pathway ,Cancer ,medicine.disease ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Cell nucleus ,medicine.anatomical_structure ,chemistry ,Cancer research ,Molecular Medicine ,Signal transduction ,Drug Screening Assays, Antitumor ,medicine.drug - Abstract
The Wnt/β-catenin pathway is often found deregulated in cancer. The aberrant accumulation of β-catenin in the cell nucleus results in the development of various malignancies. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Herein we report inhibitors of β-catenin signaling of potential therapeutic value as anticancer agents. Ethyl 4-((4-(trifluoromethyl)phenyl)sulfonamido)benzoate (compound 14) inhibits the effect on Wnt reporter with an IC50 value of 7.0 μM, significantly reduces c-MYC levels, inhibits HCT116 colon cancer cell growth (IC50 20.2 μM), does not violate Lipinski and Veber rules, and shows predicted Caco-2 and MDCK cell permeability Papp >500 nm s-1 . Compound 14 seems to have potential for the development of new anticancer therapies.
- Published
- 2020