Industry perspective on the nonclinical safety assessment of heterobifunctional degraders

• Published in: Drug discovery today 2023-08, Vol.28 (8), p.103643-103643, Article 103643
• Main Authors: Hemkens, Michelle, Stamp, Katie, Loberg, Lise I., Moreau, Kevin, Hart, Tim
• Format: Article
• Language: English
• Subjects: cereblon; crosspharma survey; Humans; IQ Consortium; off-target toxicity; preclinical safety assessment; Proteasome Endopeptidase Complex - metabolism; proteomics; species selection; targeted protein degrader
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2023.103643

•Cross-industry survey about the preclinical safety assessment of targeted protein degraders was conducted.•Safety assessments of protein degraders and typical small molecules are conceptually similar.•Key safety concern is potential off-target toxicity, including cereblon neosubstrate–mediated teratogenicity.•Proteomics is used to assess on- and off-target proteins in vitro and in vivo.•Assay/study duration is adjusted for prolonged or delayed effects. Targeted protein degraders (TPDs), which act through the ubiquitin proteasome system (UPS), are one of the newest small-molecule drug modalities. Since the initiation of the first clinical trial in 2019, investigating the use of ARV-110 in patients with cancer, the field has rapidly expanded. Recently, some theoretical absorption, distribution, metabolism, and excretion (ADME) and safety challenges have been posed for the modality. Using these theoretical concerns as a framework, the International 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 safety assessment of TPDs is the same as for standard small molecules; however, the techniques used, assay conditions/study endpoints, and timing of assessments might need to be modified to address differences in mode of action of the class.