Fig. 4, Key Figure. Summary of the SWOT analysis of targeted protein degradation.

Here we summarize the different strengths, weaknesses, opportunities and threats in the field in an attempt to help in a strategic development of the field. Key Strengths of targeted protein degradation as pharmacological and research tool modality are: (1) their unique mechanism of action (MOA) as they induce degradation of the target, therefore removing not only its activity (which is the feature inhibitors affect) but scaffolding or other roles the target may have; (2) potential to target proteins currently considered to be difficult to address using small molecules given that degrader molecules does not require tight binding or the presence of high-affinity binding pockets on the target, and (3) potential for improved selectivity and efficacy. On the other hand, major Weaknesses of degrader molecules are: (1) lack of rules and standards to guide their development and optimization, as well as sufficient numbers of E3 ligases that can be employed for degrader development; (2) concentration dependence that results in decreased activity at high concentrations called “hook effect”, which may render dosing difficult and raise concerns regarding the safety; (3) potential for chemical/synthetic complexity, something that may become increasingly important as attempts to decouple inhibitory activity from degradation activity become more prominent. In terms of Opportunities, the major ones are: (1) use of degrader molecules as research tools to better understand biological function and disease physiology, as well as potentially expand the target space; and (2) use of degraders as a test case for developing additional modalities that use similar activity-hijacking mode of action (activity-hijacking chemical inducers of dimerization (CIDs). In terms of threats, the most significant ones are: (1) biological and functional complexity of the biology coupled with potentially inflated expectations; and (2) lack of cohesive community to drive standard and technology development in a more organized and open manner. Taken together this roadmap identifies clear opportunities to explore and points to potential pitfalls to avoid in order to accelerate future growth in this area.