Senior Director, Toxicology Bristol Myers Squibb New Brunswick, New Jersey, United States
A critical consideration for nonclinical safety assessment is the relevance of the species to predict effects that may be observed in humans that are due to either on-target (pharmacologic) or off-target effects. This is of particular significance for cereblon modulators since there are known cereblon sequence differences across species that have been shown to render some species insensitive to the effects of molecular glues that utilise cereblon. Additionally, with targeted protein degraders, both aspects of the molecule must be considered, that of the target and the ligase, and both target and ligase expression and homology across species must be considered. In addition to on-target effects, assessment of any relevant off-target degradation must be considered since a species may be sensitive to degradation of the target substrate but perhaps not to other substrates of toxicological concern. This presentation will discuss case studies where in vitro, in vivo, and ex vivo approaches were used to select the relevant species for toxicology assessment of targeted protein degraders that use cereblon as a ligase, considering all of these factors.
