Drug Target Strategies
The success of small molecule therapeutics such as fulvestrant and lenalidomide, that promote ubiquitin mediated degradation of cancer related targets, has fueled an intense effort to mimic their activities with larger bispecific molecules called PROTACs (proteolysis targeting chimeras). PROTACs are engineered from two separate ligands joined by a flexible linker; one half engages the E3 ligase while the other half binds the disease relevant target protein. Proximity of a target to an E3 ligase results in ubiquitination and ultimately degradation of the disease-causing protein. Recent examples of BRD4 degrading PROTACs utilizing the ubiquitin ligases CRBN or VHL are quite potent and possess cellular activity that exceed that of the parent ligands. Thus, many new PROTACs targeting different proteins for degradation are being generated with the same or similar ligase binders, and the search for new PROTAC ligases is underway in both academia and industry.