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Proteins are large complex molecules that control many processes in the body. As enzymes, for example, they speed up the metabolism in our bodies and let us lead healthy lives. At the same time, hundreds of proteins have been identified as drivers of human disease. Despite decades of medicinal research, up to 90% of human proteins remain inaccessible for traditional drugs such as antibodies and small molecules. They have therefore been classified as ‘undruggable’.
However, due to recent leaps in research and development of new technologies, the notion of undruggability is being eroded. PROTACs®, or proteolysis-targeting chimera, are one of many upcoming approaches. They cause the degradation of undesired proteins by harnessing the power of the body's own degradation (waste disposal) machinery.
In this blog, Dr. Josef Auburger, Head of Laboratory, Lead Identification and Characterization at Bayer, and Dr. Philipp Cromm, Head of Laboratory, Synthetic Modalities at Bayer, discuss how PROTACs® allow us to reach into the undruggable space and unlock new approaches to tackling hard-to-treat diseases.
The potential of PROTACs® and how they work
Josef Auburger: The human genome codes around 20,000 proteins, a certain share of which can be linked to the onset and progression of disease. Broadly speaking, around 10% of disease-causing proteins – so called targets – can be addressed with traditional drugs that often inhibit the function of the target. This leaves around 90% of the human proteome that has not been reachable with current modalities.
PROTACs® are a new modality that may allow us to shrink this undruggable space. Unlike traditional small molecules, which need to constantly occupy a defined pocket on the protein, PROTACs® bring a disease-causing protein and an E3 ligase close to each other. In consequence, the disease-causing protein is marked for “destruction” by the cell's degradation machinery. This allows us to take aim at targets that were out of reach in the past, for example scaffolding proteins. PROTACs® are a truly exciting technology that could allow us to develop new, much-needed medicines.
Philipp Cromm: With PROTACs® we are helping the cell’s own “garbage truck” recognize a protein of interest as dispensable and mark it for destruction. The protein is then destroyed by the cells own protein degradation machinery – the ubiquitin proteasome system.
Alongside other emerging approaches, such as cell therapies, gene therapies and RNA-targeting small molecule drugs, PROTACs® are expanding the drug discovery toolbox. While we are currently focusing on addressing known disease targets, the field is gradually shifting towards applying PROTACs® to targets that we could not address before.
Philipp Cromm: For some diseases, cancer for example, it makes a lot of sense to take out the whole protein as opposed to simply inhibiting its function. This is because by degrading a protein you get rid of all its disease-causing functions, while many inhibitors can only block a single mechanism. Secondly, due to their mode of action, PROTACs® might also be administered at lower doses than inhibitors, which could help reduce side effects and the likelihood of drug resistance.
To unleash these unique therapeutic benefits, PROTACs® – like inhibitors, or any drug for that matter – need to be “drug-like”, meaning we need to optimize certain properties that affect the overall success of drug candidates in clinical trials. However, as the traits of PROTACs® also increases their molecular weight, this optimization process becomes more challenging than usual.
Josef Auburger: One further advantage might be tissue specificity: Due to their very nature, PROTACs® could have a more precise therapeutic effect than classical approaches, because they only work in the tissue where the disease target and the E3 ligase are simultaneously present.
Additionally, PROTACs® might have a longer therapeutic effect than their inhibitor “equivalents”. Inhibitors block the function of a disease-causing protein until they have been decomposed by the body. That’s why they need to be taken regularly to maintain a certain therapeutic effect. PROTACs® are also decomposed by the body, but unlike inhibitors, they degrade the protein that causes the disease. So their therapeutic effects last as long as the cell needs to resynthesize the protein.
Current focus areas
Josef Auburger: One area we are active in is oncology. Cancer continues to pose a tremendous challenge to public health, and we are convinced that PROTACs® have the potential to significantly impact drug development in this area and change the treatment landscape. We can benefit from the learnings in this area as we branch off into other therapeutic areas to explore the full potential of PROTACs®. We continue to broaden our indication spectrum and have initiated projects in other disease areas, too, such as inflammation and cardiovascular disease.
Philipp Cromm: PROTACs® are an emerging technology, and our efforts currently focus on research. We investigate the disease biology, identify appropriate treatment targets, design drug molecules and run them through hundreds of tests to prove that they are effective and safe before clinical development starts. The field has seen remarkable progress in the last decade and it will be very exciting to see how these compounds progress through the clinic.
The way ahead
Philipp Cromm: PROTACs® have exhibited their potential in pre-clinical development, now they will need to demonstrate solid clinical efficacy. As the industry advances more and more compounds to clinical trials, patient safety as well as clinical efficacy will take top priority. I am very excited about what lies ahead of us.
Josef Auburger: To fully explore the potential of PROTACs® in expanding the druggable space, we need to identify new and unprecedented starting points to synthesize PROTACs®. This will require an expansion of our lead-finding efforts and investments into new technologies. Under these conditions, I am confident that we can evolve PROTACs® into precision medicines that can reach targets we once thought were undruggable.