Abstract
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.
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