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Discovery of precision targeting EZH2 degraders for triple-negative breast cancer
Cheng Wang1, Xinye Chen1, Xingchen Liu1
1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China.
Abstract:
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 μM) and MDA-MB-468 (IC50 = 0.38 μM) 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.
Insights
New PROTACs precisely target EZH2, a protein overexpressed in triple-negative breast cancer (TNBC). This novel approach degrades the EZH2-associated PRC2 complex, offering improved efficacy for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Enhancer of Zeste Homolog 2 (EZH2) is frequently overexpressed in triple-negative breast cancer (TNBC) and other malignancies, impacting tumor progression and patient prognosis.
- Existing EZH2 inhibitors primarily target its catalytic activity, showing limited efficacy against solid tumors due to insufficient targeting of EZH2's intrinsic tumorigenic functions.
Purpose of the Study:
- To design and optimize novel Proteolysis-Targeting Chimeras (PROTACs) for precise targeting and degradation of EZH2 in TNBC.
- To evaluate the efficacy and mechanism of action of a lead PROTAC molecule, U3i, against TNBC cell lines.
Main Methods:
- Design and synthesis of EZH2-targeting PROTACs.
- Assessment of PROTAC binding affinity to the Polycomb Repressive Complex 2 (PRC2).
- In vitro evaluation of cell growth inhibition in TNBC cell lines (MDA-MB-231 and MDA-MB-468).
- Analysis of PRC2 complex degradation, apoptosis induction, and effects on normal cells.
Main Results:
- The optimized PROTAC molecule, U3i, demonstrated high affinity for the PRC2 complex (KD = 16.19 nM).
- U3i exhibited potent inhibitory effects against MDA-MB-231 (IC50 = 0.57 μM) and MDA-MB-468 (IC50 = 0.38 μM) TNBC cells, showing 20- to 30-fold greater activity than the conventional inhibitor GSK126.
- U3i effectively degraded the PRC2 complex in TNBC cells, induced apoptosis, and displayed minimal toxicity to normal cells.
Conclusions:
- U3i represents a promising therapeutic strategy for TNBC by effectively degrading the EZH2-PRC2 complex.
- The PROTAC approach offers a significant advancement over traditional EZH2 inhibitors for treating solid tumors like TNBC.
- Further investigation of U3i as an anticancer agent for TNBC is warranted.
