Discovery of the First Potent, Selective, and <i>In Vivo</i> Efficacious Polo-like Kinase 4 Proteolysis Targeting Chimera Degrader for the Treatment of <i>TRIM37</i>-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 <i>TRIM37</i>-amplified breast cancer. The development of novel and effective therapeutic strategies for <i>TRIM37</i>-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 <b>SP27</b> as the first selective PLK4 proteolysis targeting chimera (PROTAC) degrader. <b>SP27</b> exhibited effective PLK4 degradation, more potent inhibition of cell growth, and more efficient precision-therapeutic effect in the <i>TRIM37</i>-amplified MCF-7 cell line than conventional inhibitor CZS-035. Moreover, <b>SP27</b> showed 149% bioavailability after intraperitoneal administration in PK studies and potent antitumor efficacy <i>in vivo</i>. The discovery of <b>SP27</b> demonstrated the practicality and importance of PLK4 PROTAC and paved the way for studying PLK4-dependent biological functions and treat <i>TRIM37</i>-amplified breast cancer.