The article explores the impact of the natural half-life of target proteins on the efficacy of degrader agents in targeted protein degradation (TPD). Using mathematical modeling, the authors demonstrate that the half-life of a target protein significantly affects the level of protein degradation induced by a degrader agent. They find that agents that stall protein synthesis, such as GSPT1 degraders and cytotoxic compounds, can appear as effective protein degraders for short-lived proteins like MCL1 and MDM2. This is exemplified by the disappearance of these proteins upon GSPT1 degradation or treatment with cytotoxic agents like doxorubicin. The study also highlights the limitations of conventional control experiments, such as proteasome inhibition, in differentiating between bona fide degraders and artifacts. The authors propose several control experiments to distinguish true protein degraders from artifacts, including degradation time courses, competition experiments with binders, and analysis of effects on other short-lived proteins. These findings have implications for the selection of targets and the design of control experiments in TPD research.The article explores the impact of the natural half-life of target proteins on the efficacy of degrader agents in targeted protein degradation (TPD). Using mathematical modeling, the authors demonstrate that the half-life of a target protein significantly affects the level of protein degradation induced by a degrader agent. They find that agents that stall protein synthesis, such as GSPT1 degraders and cytotoxic compounds, can appear as effective protein degraders for short-lived proteins like MCL1 and MDM2. This is exemplified by the disappearance of these proteins upon GSPT1 degradation or treatment with cytotoxic agents like doxorubicin. The study also highlights the limitations of conventional control experiments, such as proteasome inhibition, in differentiating between bona fide degraders and artifacts. The authors propose several control experiments to distinguish true protein degraders from artifacts, including degradation time courses, competition experiments with binders, and analysis of effects on other short-lived proteins. These findings have implications for the selection of targets and the design of control experiments in TPD research.