The concept of using the innate UPS system is very interesting and new to me. It seems like most PROTAC E3 ligases consist of ligands for cereblon. If I were to use a different E3 ligase other than CRBN that's known to be expressed in only certain tissues of the body, would my target protein for degradation be limited to that same tissue?
Great question! Unfortunately, it's very hard to tell that in advance, and there are several pitfalls you should not forget about. Developing this (high-affinity) PROTAC is only the first milestone. Then you have to make sure you can administer it in a way that you deliver it to the target tissue and the cells have the desired uptake, which is not trivial to say the least. Many things can go wrong: your PROTAC can have bad ADMET properties, and I assume it is also hard to know in advance whether it has a significant off-target effect, i.e. it degrades other substrate proteins as well.