Discovery of a novel 2,4-thiazolidinedione derivative as dual inhibitor of β-catenin/TCF4 interaction and tubulin polymerization in colon cancer cells

Hyperactivation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Based on a previously reported lead compound, iCRT14, a series of 2,4-thiazolidinedione derivatives were designed, synthesized, and evaluated in vitro for their antiproliferative activity against colon cancer cells. Compound 15k exhibited the most potent activity against the HCT116 and SW480 cell lines. Compound 15k inhibited Wnt/β-catenin signaling by disrupting the protein–protein interactions between β-catenin and TCF4. Compound 15k simultaneously inhibited tubulin polymerization, disorganized the microtubule network, and arrested the cell cycle at the G2/M phase, offering an additional mechanism of action and 15k induced cell apoptosis by activating caspase-3 and poly(ADP-ribose) polymerase. Additionally, compound 15k inhibited cell migration without affecting the levels of β-catenin protein. These results offer guidance for developing the current series as potential new anticancer therapeutics.