ESR1 mutations and activation of growth factor signaling (e.g., PI3K-AKT) drive endocrine therapy resistance in breast cancer, largely limiting the success of breast cancer treatment. We reported a first-in-class, selective and potent BRPF1-targeted proteolysis-targeting chimera (PROTAC) B-8, and it downregulated H3K23ac and ER, causing cell cycle arrest and autophagic cell death.