This emerging field of pharmacology offers many advantages over classical inhibitor-type modalities. First destruction of a disease-driving protein eliminates all protein functions – such as scaffolding functions – achieving a much deeper pharmacological perturbation of the system. Next, degraders often elicit higher selectivity as the interactors have to be placed into the correct orientation. This enables a degree of engineerability to reduce off-target effects. Finally, by moving beyond single drug binding pockets, glue-like small molecules can also be used to target the vast space of previously considered “undruggable” proteins.
Inducing proximity is, however, by far not limited to degradation phenotypes. Recruiting alternative effectors to E3 ligases, inhibiting, activating or localization-altering perturbations can be generated. Overall, the aim is always to generate disease-specific and oncogene-specific modulations, rewiring the protein interactome and thus cellular signaling to generate new treatment modalities in the fight against cancer.