Development\nof <i>N</i>‑(4-(1<i>H</i>‑Imidazol-1-yl)phenyl)-4-chlorobenzenesulfonamide,\na Novel Potent Inhibitor of β‑Catenin with Enhanced Antitumor\nActivity and Metabolic Stability

The potential as a cancer therapeutic target of the recently\nreported\nhotspot binding region close to Lys508 of the β-catenin armadillo\nrepeat domain was not exhaustively explored. In order to get more\ninsight, we synthesized novel <i>N</i>-(heterocyclylphenyl)benzenesulfonamides <b>6</b>–<b>28</b>. The new compounds significantly\ninhibited Wnt-dependent transcription as well as SW480 and HCT116\ncancer cell proliferation. Compound <b>25</b> showed binding\nmode consistent with this hotspot binding region. Compound <b>25</b> inhibited the growth of SW480 and HCT116 cancer cells with IC<sub>50</sub>’s of 2 and 0.12 μM, respectively, and was superior\nto the reference compounds <b>5</b> and <b>5-FU</b>. <b>25</b> inhibited the growth of HCT-116 xenografted in BALB/C<sup>nu/nu</sup> mice, reduced the expression of the proliferation marker\nKi67, and significantly affected the expression of cancer-related\ngenes. After incubation with human and mouse liver microsomes, <b>25</b> showed a higher metabolic stability than <b>5</b>. Compound <b>25</b> aims to be a promising lead for the development\nof colorectal cancer anticancer therapies.