The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the beta-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 mu M, 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.
Puxeddu, M., Ling, L., Ripa, S., D'Ambrosio, M., Nalli, M., Parisi, A., Sciò, P., Coluccia, A., Granese, A., Santelli, M., Masci, D., Cuřínová, P., Naro, C., Sette, C., Pastore, A., Stornaiuolo, M., Bigogno, C., Dondio, G., Di Magno, L., Canettieri, G., Liu, T., Silvestri, R., La Regina, G., 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, <<JOURNAL OF MEDICINAL CHEMISTRY>>, 2024; (n/a): N/A-N/A. [doi:10.1021/acs.jmedchem.4c01708] [https://hdl.handle.net/10807/299018]
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
Santelli, Martina;Masci, Domiziana;Naro, Chiara;Sette, Claudio;La Regina, Giuseppe
2024
Abstract
The potential as a cancer therapeutic target of the recently reported hotspot binding region close to Lys508 of the beta-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 mu M, 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.
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