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

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 (IC = 0.028 μM) and EZH2 (IC = 0.074 μM), and the inhibitory activity against PARP2 (IC = 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.