Industry perspective on the nonclinical safety assessment of heterobifunctional degraders

Targeted protein degraders (TPDs), which act with the ubiquitin proteasome system (UPS), are among the newest small-molecule drug modalities. Because the initiation from the first medical trial in 2019, investigating using ARV-110 in patients with cancer, the area has quickly expanded. Lately, some theoretical absorption, distribution, metabolic process, and excretion (ADME) and safety challenges happen to be posed for that modality. With such theoretical concerns like a framework, the Worldwide Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) Protein Degrader Working Group (WG) conducted two surveys to benchmark current preclinical practices for TPDs. Conceptually, the security assessment of TPDs is equivalent to for normal small molecules however, the strategy used, assay conditions/study endpoints, and timing of assessments should be modified to deal with variations in mode of action from the class.