Here we present new early-stage work being done on a completely new class of RET medications: protein degraders! This class has a lot of advantages over the current RET drugs:
How do current drugs work? The RET protein has a small pocket from which the energy source enters, and that energy allows it to constantly signal for cancer growth. If you block the pocket, the energy source is not able to power the protein anymore and so RET is inactivated. This is exactly how TKIs like selpercatinib and pralsetinib work, by sticking inside that energy pocket, staying there and blocking it.
What are some of the drawbacks of the current drugs? That approach has been very successful as a lot of us here can attest, but there are some problems with it. First, finding drugs is hard: the molecule absolutely has to bind to RET's energy pocket, and be very specific to THAT pocket and no other because blocking unrelated proteins can cause side-effects. Also in resistance, the RET protein can mutate that pocket so that the drug is not able to bind to it anymore. The cancer can also produce more RET proteins so that there's not enough medication to block them all. Finally, despite having its energy source blocked, the RET protein stays inside the cell and can continue to affect other processes.
What are protein degraders? All of our cells have a built-in garbage collection system. When proteins are no longer useful, they are marked and then degraded by specialized enzymes. So could we somehow force cells to mark RET and destroy it themselves? This is exactly what degraders (which we call PROTACs) do!
How do they work? The drug consists of two warheads linked together. One head will bind to RET, and another will bind to a protein called E3. What E3 does is mark proteins so that the garbage collectors know to destroy them. The job of the drug is to bring E3 and RET close together, so that E3 starts marking it. Once that happens, RET is destroyed and the drug is free to wander around again, starting the process once again!
How is that better than current drugs? You probably already see some of the advantages. Since every PROTAC molecule can degrade many RET proteins, the doses needed are very small (i.e. less side-effects). They also don't need to be designed for the energy pocket, they can be allowed to bind anywhere on RET. Also, since they destroy the protein entirely, RET is unable to signal anything anymore. This all means that they are almost immune to the on-target resistance mechanisms which current medications suffer from.
Where are we on this? PROTACs are a relatively new idea but with a lot of promise. Some of these drugs (not for RET) are already in trials for prostate cancer targets. However it seems that this company is working on a RET-specific PROTAC and will start preclinical studies very soon.
The company’s website: https://c4therapeutics.com/pipeline
A nice video that explains things in a more visual way: https://www.youtube.com/watch?v=7vSAGU4JCTM