Protein Degraders in Drug Discovery: Mechanism, ADME Challenges, and Translational Strategies

Targeted protein degraders are emerging as a powerful new therapeutic modality, offering the potential to address disease causing proteins that have long been considered “undruggable.” However, their unique mechanisms and beyond Rule of Five properties introduce new challenges across ADME, pharmacokinetics, safety, and translation to the clinic. In this webinar, we provide a practical, science driven overview of protein degraders such as molecular glues and heterobifunctional degraders with a focus on how they differ from traditional small molecule drugs. We will present internally generated in vitro ADME data obtained with two commercially available PROTACs, ARV-825 and JNJ-1013. These data will be used to highlight key ADME characteristics, common challenges, and effective strategies to navigate them, ultimately supporting more informed decision-making in preclinical drug development. Key Topics & Takeaways: • Fundamental mechanisms of targeted protein degradation, including molecular glues and heterobifunctional degraders, and how these differ from traditional small‑molecule inhibitors. • Unique ADME and PK challenges associated with protein degraders, including permeability limitations, nonlinear PK/PD, and the hook effect. • In vitro assay limitations for protein degraders, including issues with solubility, nonspecific binding, metabolic stability, and IVIVE disconnects. • How in vitro ADME and DDI studies are applied to characterize metabolic stability, drug-drug interactions and immunological risks of degraders. • Key considerations for in vitro drug-drug-interactions and regulatory alignment when advancing protein degraders toward clinical development. Download the slides: https://info.bioivt.com/protein-degra... Additional resources on this and other topics: https://bioivt.com/resources/educatio... Questions, comments and requests: https://bioivt.com/about/contact-us Access BioIVT's products and services: https://bioivt.com Other previously aired webinars: https://bioivt.com/educational-conten...) Upcoming webinar notifications: https://bioivt.com/resources/newslett... About the Presenter Dr. Tina Mueller is a Scientific Advisor for ADME-Tox Services at BioIVT. She joined BioIVT in 2023 and consults with customers and internal teams on in vitro ADME programs with a focus on in vitro DDI studies and compliance with regulatory guidelines. Tina obtained her PhD in Biochemistry and Microbiology and earned a Master’s in Environmental Sciences from the Swiss Federal Institute of Technology in Zurich, Switzerland. Before joining BioIVT, she was an Associate Director, Research at Cybin where she led the company’s research programs from early through late discovery. Additionally, Dr. Mueller served as a Research Associate Professor at Michigan State University, Senior Staff Scientist at Scripps Florida, and Professor for Biomedical Sciences at Keiser University.