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

Abstract

Polo-like kinase 4 (PLK4) is a master regulator of centriole replication and has been proposed as a therapeutic target for multiple cancers, especially TRIM37-amplified breast cancer. The development of novel and effective therapeutic strategies for TRIM37-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 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-therapeutic effect in the TRIM37-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, SP27 showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy in vivo. The discovery of SP27 demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat TRIM37-amplified breast cancer.

Emerging roles of tripartite motif family proteins (TRIMs) in breast cancer

“…Studies revealed that TRIM37 blocks the formation of foci that comprise pericentriolar material—these foci are structures with a microtubule‐nucleating capacity, which is required for correct cell division in the absence of centrosomes. 204 , 205 Interestingly, researchers found an excess of TRIM37 leads to synthetic lethality with the polo‐like kinase 4 (PLK4) inhibitor, which provides a rationale for the use of centrosome targeting agents in treating tumors bearing TRIM37 overexpression. Notably, the TRIM37 is located in the chromosomal region 17q23, which is frequently amplified in several tumor types, including about 10% of BC cases.…”