Discovery of selective PARP1/CDK6 dual target inhibitors modulating Wnt signaling pathway for the treatment of TNBC.

The combination of PARP1 and CDK6 inhibitors shows synergistic anticancer effects in TNBC. However, first-generation PARP inhibitors lack optimal PARP trapping efficiency and enzyme family selectivity, often leading to hematotoxicity. Herein, we report the rational design and synthesis of a series of second-generation selective PARP1/CDK6 dual inhibitors, based on the structural features of the latest selective PARP1 inhibitor AZD5305. Among these, PC8 exhibits potent dual inhibition of PARP1 (IC50 = 0.126 μM) and CDK6 (IC50 = 0.197 μM), showing selectivity over PARP2 (IC50 = 0.824 μM). PC8 effectively inhibits the proliferation and migration of TNBC cells, and induces intracellular ROS accumulation, thereby exacerbating mitochondrial dysfunction and DNA damage. Additionally, it modulates the classical Wnt signaling pathway. Furthermore, compared with first-generation inhibitors, PC8 displays improved metabolic stability in liver microsomes. As a novel selective PARP1/CDK6 dual inhibitor with improved pharmacological properties, PC8 represents a promising lead structure for further optimization of second-generation PARP1/CDK6 dual inhibitors for the treatment of TNBC.