Discovery of the First Potent, Selective, and Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of -Amplified Breast Cancer.

Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially -amplified breast cancer. The development of novel and effective therapeutic strategies for -amplified breast cancer therapy is challenging and extremely desirable. Herein, a structure-activity relationship (SAR) study with an emphasis on exploring different linker lengths and compositions was performed to report the discovery and characterization of as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the -amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy . The discovery of demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat -amplified breast cancer.