PROTACs (Proteolysis-targeting chimeric molecules) artificially hijack the components of the UPS (Ubiquitin Proteasome System) to degrade a target protein, founding the concept of PROTAC Drug Discovery. PROTAC drugs are hetero-bifunctional small molecules that contain two functional ligands connected via a linker; one ligand binds to a target protein and the other ligand binds to an E3 ligase. Bringing these two entities into proximity theoretically leads to polyubiquitylation and proteasomal degradation of the target protein. However, given the complexity this scenario does not always play out, and the PROTAC discovery platform faces several challenges.

With tremendous excitement surrounding the field of targeted protein degradation, there is an unmet need for functional assays that can study the effects of PROTACs on the ubiquitination of a target(s) and subsequent degradation. Traditional methods such as western blotting and reporter gene assays have been at the forefront to study PROTAC mediated degradation. However, these methods are extremely low throughput, time-consuming, and/or prone to artifacts. LifeSensors has developed high-throughput methods to directly monitor PROTAC mediated ubiquitylation and degradation of target proteins.

LifeSensors has developed technology to specifically isolate polyubiquitylated proteins from cell lysates and tissues. TUBEs are tandem ubiquitin binding domains (UBDs) that bind poly-ubiquitin with Kds in the nanomolar range. TUBEs have also been demonstrated to protect ubiquitylated proteins from both deubiquitylation and proteasome-mediated degradation, even in the absence of inhibitors normally required to block such activities.