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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 human proteins are known to cause disease. Due to structural challenges and a lack of certain features, and despite decades of medical progress, up to 90% of human proteins have been considered inaccessible to drugs, or simply ‘undruggable’.
However, due to recent leaps in research and development of new technologies, the notion of undruggability is being eroded. One key technology is chemoproteomics, which addresses the limitations of conventional screening techniques to discover previously unknown pockets on the surface of proteins and identify small molecules that bind to those targets.
In this blog post, Dr. Knut Eis, VP Therapeutic Modalities at Bayer Pharmaceuticals, and Dr. Gabe Simon, Head of Proteomics Platform at Vividion Therapeutics, a wholly owned subsidiary of Bayer, discuss how chemoproteomics could unlock undruggable targets and generate new, much-needed therapies.
Pushing back the boundaries of druggability with chemoproteomics
Knut Eis: Many drug discovery methods are built on the requirement that there are clearly defined pockets (binding sites) on the surface of disease-causing proteins, or targets, that a drug molecule can bind to. In an effort to identify new targets and push back the boundaries of the undruggable space, we continuously explore new ways of finding and addressing these targets.
In this context, few technologies have triggered our enthusiasm as much as chemoproteomics. Chemoproteomics is a new approach to drug discovery and allows us to build a much deeper understanding of the interaction between small molecule compounds and proteins and could help us overcome long-standing constraints of traditional drug discovery approaches.
Gabe Simon: While several companies have adopted chemoproteomics as one of many approaches to drug discovery, Vividion was built around chemoproteomics and relies on it as its primary technology platform. It allows us to efficiently identify previously unknown protein pockets, even on well-studied proteins, and develop new drug compounds by combining three components:
- A novel chemoproteomics screening technology, which allows us to detect, sensitively and precisely, interactions between small molecules and proteins
- An integrated data portal, which translates the chemoproteomics data into results that can be easily interpreted by biologists and chemists
- A custom chemistry screening library comprised of tens of thousands of small molecules that are designed to bind to pockets in disease-causing proteins
These technology pillars allow us to address disease-causing proteins that, in most cases, no one has ever been able to drug before.
Advantages and therapeutic opportunities
Gabe Simon: Traditional screening approaches usually involve the search for small molecules, which disrupt a specific function of a protein, that lead to a fluorescent signal. Drugs are only detected if they interfere with that function in a specific way. By contrast, chemoproteomics is a function-agnostic approach: we look for druggable pockets anywhere on any type of protein, including proteins that are traditionally not thought of as being druggable and that don’t lend themselves to fluorescent readouts. With such an open-ended approach, we discover lots of new binding sites and compounds that are therapeutically useful, often in unexpected ways. We are not only looking under the lamppost.
Another key advantage over traditional screening approaches is that we can evaluate the behavior of proteins in their native context, like in a live cell. Screening proteins in cells allows us to evaluate their behavior in their native state, which often reveals pockets and activities that are otherwise hidden. This approach can reveal novel opportunities and greatly accelerate the drug development process.
Knut Eis: From the disease perspective, the technology has shown its applicability in oncology and immune-related diseases. While these are our current focus areas, we are also keen on exploring the opportunities in other disease areas. This includes therapy areas where Bayer has held leading positions for years, including cardiovascular disease and women’s health. Personally, I am excited to look at opportunities in all areas.
More generally speaking, I believe that chemoproteomics will re-energize research and development of small molecule therapeutics as such. With the advance of therapeutic antibodies and other types of drugs, the question has been raised whether small molecules might lose some of their relevance. I strongly disagree with this notion. In fact, chemoproteomics have gone hand in hand with a resurgence of interest particularly in small molecules, which covalently bind to their target, and I am sure that they are here to stay.
1 + 1 = 3
Knut Eis: I am convinced that Bayer’s partnership with Vividion will result in outcomes that we would not achieve otherwise. Having made inroads in chemoproteomics and enhanced our screening efforts with projects like the Next Generation Library Initiative already before the partnership, I believe that our joint efforts will pick up pace quickly.
One of the first things we are doing is to jointly drive compound library development, as this is an area that will hugely benefit from our combined expertise. We are also studying the potential of drug molecules in disease areas outside the current scope of Vividion’s focus, where Bayer holds expertise. Equally, Bayer will benefit from Vividion’s expertise in optimizing small molecules. These are just a few early examples, there will be many other synergy opportunities.
Gabe Simon: Bayer has invested heavily in building their chemical library and I am excited to expand and build new libraries together. Vividion’s unique technology allows us to strengthen library development at both organizations. Vividion brings speed and an entrepreneurial culture that we are eager to combine with Bayer’s chemical prowess. There will be many opportunities to cross-pollinate, far beyond joint library development, and I think our interaction is going to be powerful going forward.
A glimpse into the future
Knut Eis: I think the future of chemoproteomics and drug discovery is bright. As we discover more and more targets and drug compounds, we will need to optimize the way these new drug compounds behave in the human body. But these are challenges that have been solved over and over again, including with drugs that are currently on the market. These are certainly challenges we are happy to have.
Gabe Simon: I am confident that we are going to keep delivering more opportunities and targets – we have only just scratched the surface. We are steadily accessing new targets and we relentlessly focus on efficiently capitalizing on all these opportunities. There is a tremendous number of undiscovered and disease-relevant targets in the undruggable space. We are only limited by our imagination.