Design and Synthesis of c-Met and HDAC Dual Inhibitors for the Treatment of Breast Cancer

In recent years, it has been proposed that c-mesenchymal-to-epithelial transition factor (c-Met) and histone deacetylase (HDAC) dual inhibition is a promising cancer treatment strategy. Herein, a series of c-Met/HDAC dual inhibitors were designed and synthesized given their synergistic anticancer effect in breast cancer cells. Compound <b>12d</b> exhibited excellent inhibitory activity against c-Met (IC₅₀ = 28.92 nM) and HDAC (85.68%@1000 nM) and inhibited the proliferation of all three breast cancer cell lines. Moreover, a mechanism investigation demonstrated that <b>12d</b> could simultaneously induce cell cycle arrest in the G₀/G₁ phase and cell apoptosis in MDA-MB-231 cells, which was endorsed by c-Met and HDAC pathway blockade. It could also suppress cell invasion. Our results suggest that developing promising c-Met/HDAC dual inhibitors is a novel strategy for breast cancer therapy.