Principal Investigator and Director Dana-Farber Cancer Institute Boston, Massachusetts, United States
Targeted protein degradation is a clinically precedented therapeutic modality and there has been a recent surge in the rational development of degraders for oncology and non-oncology indications. This presentation will discuss the safety characteristics and challenges of molecular glue and heterobifunctional degraders. Small molecule protein degraders phenocopy genetic methods of whole protein depletion. Therefore, degraders often possess greater efficacy than protein ‘inhibitors’ that only affect one function of a target. Other attractive features of the modality include the potential to address proteins previously deemed ‘undruggable’ (such as transcription factors) and event-driven pharmacology that translates to catalytic target degradation. Notably, these pharmacological attributes, and the physicochemical characteristics of heterobifunctional degraders in particular, also affect toxicological characteristics and safety de-risking strategies. I will present recent work from our laboratory to advance safety assessments and property-based optimization of targeted protein degraders. I will also describe our development of chemogenomic and chemoproteomic platforms to explore and assess off-target degradation profiles that will be of broad interest to those working in degrader drug discovery.
