Kinetic Modeling of PROTAC-Induced Protein Degradation

Kinetics of the PROTAC-induced protein degradation were modelled using the equilibrium approximation, accounting for the protein recovery rate with a time lag. The simulated kinetic curves resemble what is experimentally observed, and the physical formulas of the half-maximal degradation concentration (DC50) were derived from them. The equations reveal that DC50 is proportional to the dissociation constant of the ternary complex (Kd) and inversely proportional to the expression level of the E3 ligase and the effective ubiquitylation rate (kub). The predicted relationships were rigorously confirmed by experimental evidences from a matched molecular pair analysis using a set of published PROTACs. The equations derived from kinetic modelling of PROTAC-induced protein degradation reveal the dependency of DC50 on the dissociation constant of the ternary complex, the expression level of the E3 ligase, and the effective ubiquitylation rate.image