Strategies for Assessing Targeted Protein Degrader Modality Safety in Drug Discovery Programs (S16-4)

Targeted protein degraders (TPDs) allow expansion into therapeutic areas beyond the traditional oncology space.  While this modality is often viewed by medicinal chemists as a small molecule therapeutic, there are additional TPD modality-specific toxicities to address. Early safety de-risking strategies can be deployed as part of the battery of discovery toxicology in vitro and in vivo assays specific to this modality. Specific modality-based risks have been identified for some cereblon E3 ubiquitin ligase degraders (cytopenia, teratogenicity, hypocalcemia), but less is known about other ligases, such as Von Hippel-Lindau (VHL). To understand this, specialized in silico approaches, and in vitro assays for degradation of known neo-substrates are useful alongside developmental toxicity assays, and focused/global proteomic approaches to assess on- and off-target degradation. Selection of appropriate cell type(s) for use for in vitro assays and species selection for short-term exploratory in vivo studies are critical. Uses and limitations in the context of an early drug discovery program will be discussed, alongside future considerations for assessing non-cereblon E3 ligases.