Fig. 3. Degrader molecules validation criteria.

A set of criteria that can help formalize the process of degrader characterization and validation. The criteria can be useful for structuring laboratory workflows, as well as for evaluating newly reported degraders. The criteria presented here are based on Collins et al. [58]. Overall, in addition to control compounds that should be used in parallel throughout the validation process (1), the workflow for degrader validation needs to include experimental evidence of: (2) target engagement and degradation; (3) target and E3 ligase binding; (4) polyubiquitination and proteasome dependence of the process; (5) cellular permeability and in-cell target selectivity; and (6) phenotype dependence on degradation.