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[Display omitted] • Novel, potent and effective EZH2 degraders were developed. • Compound P4 can effectively induce EZH2 protein degradation and inhibit breast cancer cell growth. • Compound P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G 0 /G 1 phase arrest in Pfeiffer and MDA-MB-231 cell lines. • Compound P4 significantly inhibited the migratory and invasive capacity of MDA-MB-231 cells at micromolar concentrations in a dose-dependent manner. • Adequate metabolic stability in vitro. EZH2 (enhancer of zeste homolog 2) is one of the most important histone methyltransferases (HMTs), and overexpression of EZH2 can lead to proliferation, migration and angiogenesis of tumor cells. But most of EZH2 inhibitors are only effective against some hematologic malignancies and have poor efficacy against solid tumors. Here, we report the design, synthesis, and evaluation of highly potent proteolysis targeting chimeric (PROTACs) small molecules targeting EZH2. We developed a potent and effective EZH2 degrader P4 , which effectively induced EZH2 protein degradation and inhibited breast cancer cell growth. Further studies showed that P4 can significantly decrease the degree of H3K27me3 in MDA-MB-231 cell line, induce apoptosis and G 0 /G 1 phase arrest in Pfeiffer and MDA-MB-231 cell lines. Therefore, P4 is a potential anticancer molecule for breast cancer treatment. [ABSTRACT FROM AUTHOR]