Discovery of the First Potent, Selective, and In Vivo Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of TRIM37-Amplified Breast Cancer

Polo-like kinase 4 (PLK4) is a master regulator of centriolereplicationand has been proposed as a therapeutic target for multiple cancers,especially TRIM37-amplified breast cancer. The developmentof novel and effective therapeutic strategies for TRIM37-amplified breast cancer therapy is challenging and extremely desirable.Herein, a structure-activity relationship (SAR) study withan emphasis on exploring different linker lengths and compositionswas performed to report the discovery and characterization of SP27 as the first selective PLK4 proteolysis targeting chimera(PROTAC) degrader. SP27 exhibited effective PLK4 degradation,more potent inhibition of cell growth, and more efficient precision-therapeuticeffect in the TRIM37-amplified MCF-7 cell line thanconventional inhibitor CZS-035. Moreover, SP27 showed149% bioavailability after intraperitoneal administration in PK studiesand potent antitumor efficacy in vivo. The discoveryof SP27 demonstrated the practicality and importanceof PLK4 PROTAC and paved the way for studying PLK4-dependent biologicalfunctions and treat TRIM37-amplified breast cancer.

Automated summary

A study discovered SP27 as the first selective PLK4 PROTAC degrader, which effectively degrades PLK4 and exhibits more potent inhibition of cell growth in TRIM37-amplified breast cancer. This finding is of great significance for the treatment of this cancer.