PROTACs

Traditionally, many small molecule drugs follow the same basic mechanism of action to treat diseases: They inhibit the function of a target protein that has an active role in a disease. To do so, they require a tractable active binding site to occupy, which will result in protein function inhibition like blocking its enzymatic activity. But traditional small molecules can only block one single domain function of the protein, which means that potential other functions remain intact and can continue to fuel disease processes. This is one reason why it is assumed that traditional small molecule drugs can sufficiently address only a small percentage of the disease-causing proteins in the human proteome via the described mode of action. The great majority of proteins remains in the so called “undruggable space”.

Novel chemical modalities with a different mode of action such as PROTACs^®, however, could offer a means to minimize this “undruggable space” .

Using the cell’s own waste disposal system to treat disease

PROTACs^® – short for proteolysis targeting chimeras – do not delete proteins by themselves, but instead utilize the ubiquitin proteasome system (UPS) – the natural cellular protein degradation system – to break them down. To do this, PROTACs^® molecules consist of two parts, which are connected via a linker. With one part, the target binder, PROTACs^® bind to the specific protein like traditional small molecules do. In contrast to small molecule drugs, it is not required that this binding translates into inhibition of the protein function, The other part of the PROTACs^® engages with an enzyme called E3 ubiquitin ligase bringing the target protein and the E3 ligase in close proximity – connected via the PROTAC. Consequently, the E3 ligase tags the protein to mark it for degradation by the proteasome, the cellular “waste disposal machine” that breaks down unneeded or damaged proteins.

Because of their special mode of action, PROTACs^® offer a series of advantages compared to traditional small molecule drugs: For one, they do not require to constantly occupy the functional site at the protein of interest to be effective. Also, by removing the protein of interest, all its functions are abrogated, which could lead to additional pharmacological effects compared to a traditional small molecule.

Moreover, PROTACs^® have the potential to create a longer-lasting therapeutic effect because they degrade a protein, which consequently needs to be resynthesized by the cell to be operational again. Furthermore, it is expected that they might require lower doses than traditional small molecules, since they are released after their target protein has been degraded, freeing them up to continue their mission. This potentially enhances safety margins and the risk of drug resistance occurring.

Overall, these properties make PROTACs^® a very attractive new approach for the development of novel treatment options. Especially diseases driven by an accumulation of disease proteins, as is often common to cancer could potentially benefit. At Bayer, we are also evaluating the PROTACs^® technology for the development of next-generation medicines for patients with cardiovascular and gynecological diseases.

A new tool in the fight against diseases

In the long run, however, PROTACs^® are not expected to replace traditional small molecules. Modern approaches are currently reviving the potential of small molecules in various conditions, they will continue to evolve and give rise to many new treatments. For many other diseases, however, PROTACs^® could offer a promising new solution. The technology platform has been shown to be robust, demonstrating high potency and durability in the preclinical setting and we are keen to explore the full potential of this novel approach. Alongside other technologies like RNA-targeting small molecules and in combination with drug discovery technologies like chemoproteomics, PROTACs^® give hope to patients suffering from many diseases that are yet considered “intractable”.