SPR-Measured Dissociation Kinetics of PROTAC Ternary Complexes Influence Target Degradation Rate.

ABSTRACT: Bifunctional degrader molecules, known as proteolysis-targeting chimeras (PROTACs), function by recruiting a target to an E3 ligase, forming a target/PROTAC/ligase ternary complex. Despite the importance of this key intermediate species, no detailed validation of a method to directly determine binding parameters for ternary complex kinetics has been reported, and it remains to be addressed whether tuning the kinetics of PROTAC ternary complexes may be an effective strategy to improve the efficiency of targeted protein degradation. Here, we develop an SPR-based assay to quantify the stability of PROTAC-induced ternary complexes by measuring for the first time the kinetics of their formation and dissociation in vitro using purified proteins. We benchmark our assay using four PROTACs that tar

SUBMITTER: Roy MJ 

PROVIDER: S-EPMC6423499 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature