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Discovery of selective PARP1/EZH2 inhibitor inducing PANoptosis in triple-negative breast cancer
Heqing Fan1, Fangbo Deng2, Yiling Lai1
1School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People's Republic of China.
Abstract:
Combination of PARP and EZH2 inhibitors has demonstrated synergistic anticancer activity in triple-negative breast cancer (TNBC). However, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family and were prone to causing hematotoxicity. In this study, we combined the structure of the latest second-generation selective PARP1 inhibitor AZD5305 to design and synthesize a series of second-generation selective PARP1/EZH2 dual inhibitors. Among these, PE31 exhibited potent inhibitory activity against PARP1 (IC50 = 0.028 μM) and EZH2 (IC50 = 0.074 μM), and the inhibitory activity against PARP2 (IC50 = 0.414 μM) is relatively weak. PE32 can effectively inhibit the proliferation and migration of TNBC cells, and can induce PANoptosis in TNBC cells, increase the level of reactive oxygen species, and activate related inflammatory pathways. Meanwhile, compared with the previous first-generation inhibitors, its permeability has improved, but its overall pharmacokinetic characteristics still need to be further optimized. However, as a novel selective PARP multifunctional molecule, it remains a highly promising potential compound for the for the treatment of TNBC.
Insights
Researchers developed novel dual PARP1/EZH2 inhibitors for triple-negative breast cancer (TNBC). These compounds show potent anticancer activity by inducing cell death and activating inflammatory pathways, offering a promising new treatment strategy for TNBC.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- First-generation PARP inhibitors for triple-negative breast cancer (TNBC) had limitations in selectivity and caused hematotoxicity.
- Combining PARP and EZH2 inhibitors shows synergistic anticancer effects in TNBC.
Purpose of the Study:
- To design and synthesize novel second-generation selective PARP1/EZH2 dual inhibitors.
- To evaluate the efficacy of these dual inhibitors in inhibiting TNBC cell proliferation and migration.
Main Methods:
- Structure-based design and synthesis of dual PARP1/EZH2 inhibitors.
- In vitro assays to determine inhibitory activity (IC50) against PARP1, PARP2, and EZH2.
- Cell-based assays to assess inhibition of proliferation, migration, and induction of PANoptosis.
Main Results:
- PE31 demonstrated potent inhibition of PARP1 (IC50 = 0.028 μM) and EZH2 (IC50 = 0.074 μM) with weak PARP2 inhibition (IC50 = 0.414 μM).
- PE32 effectively inhibited TNBC cell proliferation and migration, induced PANoptosis, increased reactive oxygen species, and activated inflammatory pathways.
- Improved cell permeability was observed, but pharmacokinetic characteristics require further optimization.
Conclusions:
- Novel selective PARP1/EZH2 dual inhibitors show significant potential for TNBC treatment.
- PE32 represents a promising multifunctional molecule for TNBC therapy, despite needing pharmacokinetic optimization.
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