Discovery of precision targeting EZH2 degraders for triple-negative breast cancer

EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2. The most active PROTAC molecule U3i has a high affinity for PRC2 complex (KD = 16.19 nM) and show good inhibitory effects on MDA-MB-231 (IC50 = 0.57 mu M) and MDAMB-468 (IC50 = 0.38 mu M) cells. Compared with that of the GSK126, the growth inhibitory activities of U3i against these two TNBC cells increased by approximately 20- and 30-fold. Further studies showed that U3i can degrade PRC2 complex in TNBC cells, induce apoptosis, and cause little damage to normal cells. Therefore, U3i is a potential anticancer molecule for TNBC treatment.

Automated summary

EZH2 is often overexpressed in TNBC and other tumors, affecting tumor development and prognosis. The designed PROTACs molecule U3i precision targets EZH2 and shows good inhibitory effects on TNBC cells, inducing apoptosis without causing much damage to normal cells. U3i is a potential anticancer molecule for TNBC treatment.