BET-HDAC Dual Inhibitors for Combinational Treatment of Breast Cancer and Concurrent Candidiasis.

Breast cancer is susceptible to Candida infections, and candidiasis has an enhancing effect on the progression and metastasis of tumor. Breast cancer and concurrent candidiasis represent a significant challenge in clinical therapy. Herein, a series of novel small molecule inhibitors simultaneously targeting bromodomain and extra-terminal (BET) and histone deacetylase (HDAC) were designed for combinational treatment of breast cancer and resistant Candida albicans infections. Among them, compounds 13c and 17b exhibited excellent and balanced inhibitory activity against both BET family proteins BRD4 and HDAC1. As compared with BRD4 or HDAC1 inhibitors, dual inhibitors 13c and 17b displayed improved in vivo antitumor efficacy in MDA-MB-231 breast cancer xenograft models. Notably, they synergized with fluconazole (FLC) to effectively reduce the kidney fungal burden in a murine model of disseminated candidiasis. Thus, the BET-HDAC dual inhibitors represented a novel therapeutic strategy for combinational treatment of breast cancer and concurrent candidiasis.