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.