Fig. 2 |. Event-driven versus occupancy-driven pharmacology.

a | According to the occupancy-driven pharmacological paradigm, small-molecule inhibitors must maintain target-protein occupancy for a sustained antagonistic effect. Moreover, noncatalytic, scaffolding functions of the target protein can be retained and thus continue to contribute to oncogenesis. Furthermore, specific catalytic inhibition of a target protein at the active site, without cross-reactivity within the same protein family, is often challenging. In the figure, the blue shapes represent target proteins, with the active site at the right side and degrader-binding site at the bottom. The blue square represents a separate protein that is able to bind to the target protein regardless of inhibitor occupancy at the active site. The green shape illustrates a protein of the same family as the target that is subject off-target effects of the inhibitor, owing to active site homology, but lacks the degrader-binding site and would, therefore, be spared from off-target degrader effects. b | Degrader drugs deplete the target protein, and functional target inhibition persists until the protein is re-synthesized, constituting an example of event-driven pharmacology. Degraders have a selectivity advantage by mediating ligase–drug–target ternary complex formation using surface interfaces that are generally broader and less conserved than active sites.