Novel dual inhibitor targeting CDC25 and HDAC for treating triple-negative breast cancer

Triple-negative breast cancer (TNBC) poses a significant challenge for treatment due to its aggressive nature and the lack of effective therapies. This study developed dual inhibitors against cell division cycle 25 (CDC25) and histone deacetylases (HDACs) for TNBC treatment. CDC25 phosphatases are crucial for activating cyclin-dependent kinases (CDKs), the master regulators of cell cycle progression. HDACs regulate various biological processes by deacetylating histone and non-histone proteins, affecting gene expression, chromatin structure, cell differentiation, and proliferation. Dysregulations of HDACs and CDC25s are associated with several human malignancies. We generated a group of dual inhibitors for CDC25 and HDAC by combining the molecular structures of CDC25 (quinoline-5,8-dione) and HDAC (hydroxamic acid or benzamide) pharmacophores. The newly developed compounds were evaluated against solid-tumor, leukemia, and non-malignant breast epithelial cells. Among the synthesized compounds, 18A emerged as a potent inhibitor, demonstrating significant cytotoxicity against TNBC cells, superior to its effects on other cancer types while sparing non-malignant cells.18A possessed similar HDAC inhibitory activity as Entinostat and potently suppressed the CDC25 activity in cells. Additionally, 18A hindered the progression of S and G₂/M phases, caused DNA damage, and induced apoptosis. These findings suggest that 18A holds promise as a targeted therapy for TNBC and warrants further preclinical development.