Selectivity through Targeted Protein Degradation (TPD).

Targeted protein degradation has become a reliable tool in the medicinal chemist's toolbox, as seen with rapid progression of PROTACs (proteolysis targeting chimeras) to clinic. Degraders have unique advantages to target proteins with no functional consequence or scaffolding function to achieve the desired phenotype. In some cases, selectivity was achieved among closely related targets. While the prospective design of degraders to achieve selectivity remains empirical, this Miniperspective analyzes some reported examples to gather key factors that are hypothesized to contribute to selectivity. Ternary complex conformation to access key lysine residues stands out as a potential key contributor. However, protein and E3 ligase expression levels, differential tissue expression, resynthesis rate, ubiquitination rate, and the stability of the ternary complex formed all have the potential to play a significant role. With continued progress in ternary structure determination along with several predictive modeling methods, a rational approach to achieve degradation and selectivity is tantalizingly close.