Protein Degraders, the Newest Players in Targeted Cancer Therapy
These molecular invaders help send cancer cells down the garbage disposal, but will they work in patients?
Some people assume drugs that specifically seek out cancer cells (and not normal cells) are relatively new inventions. In truth, targeted therapy has been a cornerstone of cancer treatment since the 1970s, when the idea of using drugs or molecules to stop tumors from making new blood vessels was proposed.
Today, the two main modalities in the field, monoclonal antibodies and small molecule drugs, bind to the target and block the downstream signaling. But more recently a third class of molecules (consisting of two small molecules attached to each other) has emerged that uses a much different strategy. These so-called protein degraders destroy rather than inhibit their target’s functionality. They also bind to parts of the protein where other drugs cannot. If they ultimately are proven to work in the clinic, it could be a huge step forward, not just for cancer research but for other diseases as well.
The first round of compounds are now in clinical trials. These drugs include Connecticut-based Arvinas’ ARV-110, designed to treat men with metastatic castration-resistant prostate cancer. ARV-110 belongs to a class of peptidic chimeric molecules called PROTACs (proteolysis-targeting chimeric molecules), bifunctional molecules that bind with one arm to the androgen receptor and the other to an E3 ubiquitin ligase. The ligase tags the target with ubiquitin, marking it for disposal by the cell’s proteasomal machinery. Imagine this process as a magnetic device collecting all metallic items and putting them in the garbage afterwards.
Another class of molecules similar to PROTACS are SNIPERs (Specific and Nongenetic inhibitor of apoptosis proteins (IAP)-dependent Protein Erasers). They recruit IAP ubiquitin ligases to effect degradation of the target protein. In each case the compounds specifically induce polyubiquitylation and proteasomal degradation of the target protein, resulting in cell death or at least growth arrest. They can also block the machinery that otherwise deubiquitylates and saves cancer specific proteins from destruction. These deubiquitylating (DUB) inhibitors are currently in preclinical development and have shown significant reduction of tumor growth in a number of cell-based and animal models.
Despite apprehension from experts in the field, due to the exceptional chemical structure of the molecules, the oral availability, solubility, resistance towards metabolic processes and in some cases their ability to cross the blood-brain barrier have turned out to be excellent for PROTACs. As it is difficult to predict chemical properties for new classes of molecules simply from their chemical structure, a lot of basic research has to be performed to optimize these compounds. In fact, it is essential to bring the target cell and the ligase in close proximity to each other, and to activate the ubiquitin system.
The beauty of the system is based on the fact that targeted degraders can bind to any nook or in any niche of the target to induce degradation. Unlike classic targeted agents, these compounds don’t need to identify specific catalytic sites or activate binding pockets. This opens up a wide variety of possible targets previously defined as undruggable. One restriction still comes with the approach; the target has to have a known ligand which unfortunately excludes a number of well-known but undruggable targets, such as the most frequently deregulated proto-oncogene MYC.
Up until now there hasn’t been much data available on the pharmacodynamic and pharmacokinetic properties of protein degraders. The first-in-class molecule Fulvestrant, an estrogen receptor degrader for women with breast cancer, had less optimal characteristics lacking oral availability and a complete degradation of the estrogen receptor, but the second generation protein degraders now entering the clinic have more appealing pharmacological features.
Beyond cancer, protein degraders also have the capability to push drug development in Alzheimer’s and Parkinson’s disease, where the blood-brain penetration characteristics appear favorable.
In short, protein degraders are opening up an additional avenue for oncology drug development. We should know soon if these drugs pan out.