2. Academic Validation
  3. Discovery of selective PARP1/EZH2 inhibitor inducing PANoptosis in triple-negative breast cancer

Discovery of selective PARP1/EZH2 inhibitor inducing PANoptosis in triple-negative breast cancer

  • Eur J Med Chem. 2026 Jan 15;302(Pt 2):118287. doi: 10.1016/j.ejmech.2025.118287.
Heqing Fan 1,  Fangbo Deng 2,  Yiling Lai 1,  Quan Liu 1,  Dexiang Hu 2,  Xudong Wang 2,  Renxin Jiang 1,  Na Li 3,  Fanglan Liu 3,  Chunhua Xia 3,  Huali Yang 4,  Cheng Wang 5
Affiliations

Affiliations

  • 1 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People's Republic of China.
  • 2 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, Shenyang, 110016, People's Republic of China.
  • 3 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People's Republic of China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, Jiangxi, 330031, People's Republic of China.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Liaoning, Shenyang, 110016, People's Republic of China. Electronic address: [email protected].
  • 5 School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330031, People's Republic of China; Key Laboratory of New Drug Transformation and Evaluation of Jiangxi Province, Nanchang, Jiangxi, 330031, People's Republic of China. Electronic address: [email protected].
PMID: 41176893 DOI: 10.1016/j.ejmech.2025.118287
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.

Keywords

Inhibitor; PANoptosis; PARP1/EZH2; TNBC.

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