PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives

Abstract

Ovarian cancer is the deadliest gynecologic malignancy. The majority of patients diagnosed with advanced ovarian cancer will relapse, at which point additional therapies can be administered but, for the most part, these are not curative. As such, a need exists for the development of novel therapeutic options for ovarian cancer patients. Research in the field of targeted protein degradation (TPD) through the use of proteolysis-targeting chimeras (PROTACs) has significantly increased in recent years. The ability of PROTACs to target proteins of interest (POI) for degradation, overcoming limitations such as the incomplete inhibition of POI function and the development of resistance seen with other inhibitors, is of particular interest in cancer research, including ovarian cancer research. This review provides a synopsis of PROTACs tested in ovarian cancer models and highlights PROTACs characterized in other types of cancers with potential high utility in ovarian cancer. Finally, we discuss methods that will help to enable the selective delivery of PROTACs to ovarian cancer and improve the pharmacodynamic properties of these agents.

Keywords: PROTAC; high-grade serous ovarian cancer; ovarian cancer; targeted protein degradation.

Figure 1

PROTAC structure and mechanism of action (MOA): (A) the PROTAC structure includes a warhead that binds the POI, a linker, and an E3 ligase ligand; and (B) the PROTAC MOA includes the formation of a ternary complex comprised of the POI, the PROTAC, and the E3 ligase. The transfer of Ubiquitin to the POI leads to its proteolytic degradation by the proteosome, while the PROTAC is recycled and can engage another molecule of POI. Figure created with BioRender.com.

Figure 2

Biological effects of PROTACs tested in EOC models. Figure created with BioRender.com.

Figure 3

Methods to improve selective delivery of PROTACs in EOC: (A) conjugation of folate to PROTACs results in selectivity for cells expressing FRα; (B) inorganic, lipid-based, and polymeric nanoparticle-based PROTAC delivery; (C) conjugation of PROTACs to antibodies facilitates selective delivery; and (D) light irradiation removes the caging group on opto-PROTACs, activating the PROTAC. Created with BioRender.com.