Current Practices and Considerations for Preclinical Safety Assessment of Targeted Protein Degraders

Registration is required for this free webinar 

Hosted by the SOT Women in Toxicology Special Interest Group and Drug Discovery Specialty Section 

Part 2 of the WIT-DDTSS Protein Degrader Webinars

Targeted protein degraders are an emerging small molecule drug modality with transformative therapeutic potential. Currently, most degraders are developed for severe life-threatening disorders and engage the E3 ligase cereblon. One barrier to the broader use of degraders is the potential risk of embryofetal toxicity with cereblon-engaging degraders, exemplified by thalidomide. Thalidomide (and analogs, known as immunomodulatory drugs) binds cereblon and modifies its substrate repertoire, leading to degradation of intended and multiple unintended neosubstrates. Some cereblon-engaging degraders have been engineered to avoid the degradation of unintended neosubstrates implicated in teratogenicity, specifically SALL4. Mechanistic links between SALL4 degradation by thalidomide and human teratogenicity have been established; further, SALL4 degradation by thalidomide (and its analogs) has been linked to teratogenicity in susceptible nonclinical species. It is generally accepted that SALL4 degradation is unlikely to be the only mechanism of teratogenicity associated with thalidomide and its analogs. Currently, best practices to evaluate the teratogenicity risk of cereblon-engaging degraders have not been established. Here, we present points to consider in the teratogenicity safety assessment of cereblon-engaging degraders from the perspective of an IQ Consortium working group. 

This presentation provides an overview of current practices employed across the pharmaceutical industry and academia to identify and evaluate potential safety concerns associated with TPDs. Insights from stakeholders were gathered through workshops highlighting emerging strategies such as proteomics-based target profiling, degrader selectivity assessment, and species selection for in vivo studies. In addition, case studies and a stakeholder survey were used to collect detailed input on study design considerations, including the use of in vitro systems, analytical methodologies, in vivo selectivity profiling, and data interpretation. Together, these efforts provide a snapshot of safety evaluation strategies currently in use and identify key challenges in translating mechanistic insights into predictive toxicology frameworks. Overall, current practices reflect a pragmatic integration of established small molecule safety principles with emerging, modality-specific approaches tailored to TPDs. 

Speakers 

Katie Stamp, PhD, Bristol Myers Squibb 

Lise Loberg, PhD, Abbvie