Kinetic Modeling of PROTAC-Induced Protein Degradation

ChemMedChem. 2023 Oct 31:e202300530. doi: 10.1002/cmdc.202300530. Online ahead of print.ABSTRACTKinetics of the PROTAC-induced protein degradation was modelled with 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.PMID:37905604 | DOI:10.1002/cmdc.202300530

Source: ChemMedChem - October 31, 2023 Category: Chemistry Authors: Hongtao Zhao Frank Narjes Source Type: research