Targeted protein
degradation (TPD) is an emerging pharmacologic
strategy. It relies on small-molecule “degraders” that
induce proximity of a component of an E3 ubiquitin ligase complex
and a target protein to induce target ubiquitination and subsequent
proteasomal degradation. Essentially, degraders thus expand the function
of E3 ligases, allowing them to degrade proteins they would not recognize
in the absence of the small molecule. Over the past decade, insights
gained from identifying, designing, and characterizing various degraders
have significantly enhanced our understanding of TPD mechanisms, precipitating
in rational degrader discovery strategies. In this Account, I aim
to explore how these insights can be extrapolated to anticipate both
opportunities and challenges of utilizing the overarching concept
of proximity-inducing pharmacology to manipulate other cellular circuits
for the dissection of biological mechanisms and for therapeutic purposes.