TY - JOUR
T1 - 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
AU - Puxeddu, Michela
AU - Ling, Lele
AU - Ripa, Silvia
AU - D’Ambrosio, Michele
AU - Nalli, Marianna
AU - Parisi, Anastasia
AU - Sciò, Pietro
AU - Coluccia, Antonio
AU - Granese, Arianna
AU - Santelli, Martina
AU - Masci, Domiziana
AU - Cuřínová, Petra
AU - Naro, Chiara
AU - Sette, Claudio
AU - Pastore, Arianna
AU - Stornaiuolo, Mariano
AU - Bigogno, Chiara
AU - Dondio, Giulio
AU - Di Magno, Laura
AU - Canettieri, Gianluca
AU - Liu, Te
AU - Silvestri, Romano
AU - La Regina, Giuseppe
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - inglese
KW - inglese
UR - http://hdl.handle.net/10807/299018
U2 - 10.1021/acs.jmedchem.4c01708
DO - 10.1021/acs.jmedchem.4c01708
M3 - Article
SN - 1520-4804
SP - N/A-N/A
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
ER -