Chair:

Ruth Roberts, ApconiX

Co-Chair:

Connie Mitchell, HESI

Primary Endorser: Drug Discovery Toxicology Specialty Section


Endorser(s): Clinical and Translational Toxicology Specialty Section


Endorser(s): Regulatory and Safety Evaluation Specialty Section

Targeted protein degraders are rapidly evolving classes of drugs with great promise to address difficult drug targets in oncologic and non-oncologic disease. However, there is limited public discussion or scientific consensus on the application of rigorous, consistent, and effective methods for assessment of their clinical safety. Molecular glues, heterobifunctional degraders, and other targeted protein degraders use endogenous protein degradation processes to target previously undruggable sites and diverse therapeutic protein targets with therapeutic potential. The goal of this Workshop is to discuss the preclinical and translational safety assessment of heterobifunctional degraders (often called proteolysis targeting chimeras or PROTACS) and molecular glues, focusing on the key challenges of early de-risking, species selection, and clinical translation. The first speaker will provide an introduction to the topic, including a description of the different approaches to targeted protein degradation, illustrated by recent data on functional genomic profiling of molecular glues and PROTACs. The second speaker will address early de-risking strategies, focusing specifically on the use of a novel proteomic platform to identify off-target proteins associated with therapeutic modalities that induce protein degradation and gene silencing. The third speaker will discuss strategies for assessing the safety of targeted protein degraders in drug discovery, including the discussion of in vitro assays to inform in vivo studies. The fourth speaker will address the challenge of selecting pharmacologically relevant species to address the toxicity of targeted protein degraders by using cereblon (a commonly utilized E3 ligase) as a case study. The final speaker will present a regulatory perspective on the challenges and opportunities of protein degradation therapies. The roundtable discussion will focus on key points raised during the Workshop, with a specific emphasis on how approaches used for targeted protein degraders may differ from those used for traditional small molecule development. Overall, this Workshop will be of great interest to the many biotech and pharmaceutical companies that are engaged in this area and to the regulators involved in supporting these programs. The Workshop also will be of great relevance to academics researching protein degradation mechanisms and their translation to therapeutics.

IAT ITS Designation: Innovations in Applied Toxicology (IAT)