Development of N‑(4-(1H‑Imidazol-1-yl)phenyl)-4-chlorobenzenesulfonamide, a Novel Potent Inhibitor of β‑Catenin with Enhanced Antitumor Activity and Metabolic Stability

• Published in: Journal of medicinal chemistry 2024-11, Vol.67 (22), p.20298-20314
• Main Authors: Puxeddu, Michela, Ling, Lele, Ripa, Silvia, D’Ambrosio, Michele, Nalli, Marianna, Parisi, Anastasia, Sciò, Pietro, Coluccia, Antonio, Granese, Arianna, Santelli, Martina, Masci, Domiziana, Cuřínová, Petra, Naro, Chiara, Sette, Claudio, Pastore, Arianna, Stornaiuolo, Mariano, Bigogno, Chiara, Dondio, Giulio, Di Magno, Laura, Canettieri, Gianluca, Liu, Te, Silvestri, Romano, La Regina, Giuseppe
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01708

The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the β-catenin armadillo repeat domain was not exhaustively explored. In order to get more insight, we synthesized novel N-(heterocyclylphenyl)­benzenesulfonamides 6–28. The new compounds significantly inhibited Wnt-dependent transcription as well as SW480 and HCT116 cancer cell proliferation. Compound 25 showed binding mode consistent with this hotspot binding region. Compound 25 inhibited the growth of SW480 and HCT116 cancer cells with IC50’s of 2 and 0.12 μM, respectively, and was superior to the reference compounds 5 and 5-FU. 25 inhibited the growth of HCT-116 xenografted in BALB/Cnu/nu mice, reduced the expression of the proliferation marker Ki67, and significantly affected the expression of cancer-related genes. After incubation with human and mouse liver microsomes, 25 showed a higher metabolic stability than 5. Compound 25 aims to be a promising lead for the development of colorectal cancer anticancer therapies.