Amarnath Natarajan

PROTACs in Ovarian Cancer: Current Advancements and Future Perspectives

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.

Symbiotic prodrugs (SymProDs) dual targeting of NFkappaB and CDK

AbstractThe release of an active drug from the prodrug generates a pro‐fragment that typically has no biological activity and could result in adverse effects. By combining two drugs, wherein each drug acts as a pro‐fragment of the other drug will eliminate the pro‐fragment in the prodrug. As they are prodrugs of each other and are symbiotic, we termed these as symbiotic prodrugs (SymProDs). To test this idea, we generated SymProDs using NFκB inhibitors that contain the reactive α‐methylene‐γ‐butyrolactone moiety and CDK inhibitors with solvent exposed secondary nitrogen atoms. We show that secondary amine prodrugs of α‐methylene‐γ‐butyrolactone containing NFκB inhibitors undergo slow release over a 72 hr period. Using an alkyne‐tagged secondary amine prodrug of α‐methylene‐γ‐butyrolactone containing NFκB inhibitor, we demonstrate target engagement. The NFκB‐CDK SymProDs were ~20‐ to 200‐fold less active against the corresponding CDK inhibitors in in vitro CDK kinase assays. Growth inhibition studies in a panel of ovarian cancer cell lines revealed potency trends of the SymProDs mirrored those of the single treatments suggesting their dissociation in cells. In conclusion, our results suggest that SymProDs offer a productive path forward for advancing compounds with reactive functionality and can be used as dual targeting agents.