A new substance library will accelerate drug research and development
Many drugs are based on small molecules. They release their healing effect in the body by activating or inhibiting a protein. In the search for new drugs, the EUbOPEN research consortium is developing selective chemical tools to modulate 1,000 target proteins – irrespectively of whether the extent of these target proteins’ involvement in certain disease processes is already known or not.
The road to a new drug is long and winding. It is not uncommon for ten to twenty years to pass between initial idea and treatment of patients. First, a suitable chemical molecule must be found. The chosen candidate is then studied in test tubes, computer simulations and animal models to determine whether it is fundamentally suitable for use in organisms, followed by testing on humans in clinical trials. These tests must demonstrate the efficacy, safety, tolerability and efficiency of the active substance, as well as the correct dosage. Only then can the new active substance be approved as a drug for general use.
Alone the search for drug candidates takes years. Academic institutions play an important role in this process because their basic research often creates the scientific foundation for pharmaceutical companies to develop active substances into medical products ready for approval. To identify a drug candidate, scientists screen up to several million chemical compounds, and if one of them proves usable, at least in principle, thousands of molecules are synthesized that closely match this master copy so that an ideal candidate can be developed from them. It is essential that an active substance not only restores a person’s health, it must also be tolerated well and cause as few side effects as possible. The best ones are those that act precisely and exclusively at a protein, the so-called drug target, responsible for the respective disease.
New approach in the search for active substances
Thanks to new insights in modern cell biology, scientists are gaining an ever better understanding of how drugs unfold their effect in the body’s cells. Here, small molecules are often used that dock onto a protein and in this way activate or inhibit it. If the target protein is responsible for headaches, for example, it is inhibited so that the pain subsides. The mode of action of drugs is highly complex because in most cases a large number of proteins are involved in the development of a disease. This is not surprising, as around 20,000 different proteins are present in a human cell: They read the genetic information in the cell nucleus, for example, regulate the metabolic processes in the cell body, or take care of communication with neighboring cells via the cell membrane. However, the role played by most of these proteins in the cell and in disease development is often unknown or at least not sufficiently understood, and this makes it difficult to assess which target protein to choose for developing a drug. As a result, pharmacologists have often developed active substances against target proteins that have only proven to be ineffective in curing the disease at a very late stage in the clinical trials. Because the path to developing a new drug is very long, such errors turn out to be very costly.
The EUbOPEN research consortium led by Goethe University Frankfurt has adopted a new methodology to support and accelerate basic research on active pharmaceutical ingredients. The basic idea is as follows: Instead of developing a single active substance against a specific target protein to treat a disease, the researchers want first to identify a large number of different small molecules that can switch a target protein on or off in a highly selective way (i.e. without affecting other proteins). The scientists call these molecules “chemical probes”. These chemical probes make it possible to test the role of many target proteins in cellular disease models at the same time and in this way identify the best therapeutic approach.
Collection of small molecules
The vision is a collection of small molecules that is as comprehensive as possible, where each individual molecule is capable of activating or inhibiting a selected protein in the human cell. Stefan Knapp, Professor of Pharmaceutical Chemistry at Goethe University Frankfurt, describes this as a toolbox that will help in the development of new drugs: “The collection of highly selective small molecules that we are working on does not yet contain any medical agents that are sufficiently optimized to treat humans. It’s more like a toolbox: If you know that a certain protein plays a role in a disease, you can revert to our toolbox and find a small molecule there that you can use to activate or inhibit the activity of the disease-relevant protein. The small molecule is then a good starting point for developing a clinically effective drug against the disease in question.”
How this toolbox is applied in practice can be illustrated using the example of leukemia, a type of cancer with dozens of subtypes for which hardly any targeted drugs are so far available. The procedure – explained in simple terms – is as follows: All the small molecules from the toolbox are applied to tissue samples of a leukemia subtype. If one (or several) of the small molecules is seen to have an effect on the cancer cell, it is possible to conclude which protein is responsible for the disease because the active substances are highly selective. “This gives medicinal chemists a good indication of which protein or proteins they can work with to develop a drug against this specific type of leukemia,” says Stefan Knapp.
1,000 target proteins
Developing this toolbox is the key objective of the EUbOPEN collaborative research project, of which Stefan Knapp is the academic coordinator. EUbOPEN is the acronym for “Enabling and Unlocking biology in the OPEN”, where “open” refers to open science. Sixteen academic institutions and five industrial partners are participating in EUbOPEN alongside Goethe University Frankfurt. The five-year research project has a budget of €65.8m. The main source of funding is the Innovative Health Initiative (IHI), which enjoys the support of the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA).
EUbOPEN started in 2020. By the end of the project, the toolbox should contain 5,000 small molecules that activate or inhibit 1,000 target proteins – this is about a third of all the proteins in the cell that can currently be modulated with small molecules. To develop the toolbox, the research group in Frankfurt led by Stefan Knapp is working closely with the University of Oxford. The researchers in England are contributing small molecules for 300 of the 1,000 target proteins. The Karolinska Institutet in Stockholm is responsible for a further 200 target proteins. Goethe University Frankfurt will develop and characterize small molecules for the remaining 500 target proteins. The pharmaceutical industry is supporting the project by contributing chemical probes from its own chemical toolboxes. Thanks to EUbOPEN’s open science character, the global research community can access all the data immediately and without restriction. This not only makes drug research more efficient but also avoids duplication, a potential outcome of data secrecy. One year before the end of the project in spring 2025, the scientists have completed 80% of their work.
High-throughput chemical probe characterization
Around 20 chemists, cell biologists and other specialists from Stefan Knapp’s group at the Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, are involved in the EUbOPEN project. The starting point for the small molecules is substances synthesized in their own laboratory or provided by other research institutions or industry. The feedstock is analyzed in terms of its chemical structure, purity, toxicity and stability, among other things. Using standardized equipment (“assays”), the team is able to screen 384 compounds simultaneously. To find 5,000 small molecules, they are obliged to comb through a much larger number of chemical compounds. All test results are documented in a database and freely accessible to researchers worldwide.
The EUbOPEN project also takes target proteins into consideration that have not yet been in the spotlight of drug development. These especially include two new families of target molecules: First, E3 ligases, which regulate protein degradation in the cell and play a role in diseases such as Parkinson’s (see also “Taking out the pathogens” on p. 51), and second, SLC (solute carrier) transporters, which are active in the cell membrane. Scientists believe that both protein families have great potential for the development of new drugs, but no efficient and selective compounds have so far been developed for most members of these protein families.
Cancer research expertise in Frankfurt
The conditions in Frankfurt for conducting basic research in the field of pharmaceutical chemistry are excellent: The university collaborates with University Hospital Frankfurt and Georg-Speyer-Haus (Institute for Tumor Biology and Experimental Therapy) under the umbrella of the “Frankfurt Cancer Institute” (see also “Bad neighbors”, p. 29), among other partners. The link to clinical practice ensures that academic research has access to cancer cells from patients. “Collaboration in the field of oncology works very well here in Frankfurt. To implement complex projects like EUbOPEN, we need a network of experts on site who think alike and contribute their specialist knowledge,” says Stefan Knapp.
EUbOPEN is an intermediate step toward the long-term objective that the “Target 2035” initiative wants to achieve by the middle of the next decade: By then, chemical probes or other small molecules should be available for all 3,000 to 4,000 potential target proteins whose activity, according to current knowledge, can be modulated with conventional small molecules. A well-stocked toolbox would then be on hand for developing drugs that not only combat new diseases but also – so scientists hope – enable personalized therapies that take the genetically determined subtype of the disease and the patient’s individual circumstances into account, for example.
Blueprint for future research partnerships
The EUbOPEN project is being implemented under the umbrella of the “Structural Genomics Consortium”. Since its establishment in 2004, this consortium has carried out several large-scale research projects as public-private partnerships. In each case, this has involved basic research, an area in which the companies are not in competition with each other and patent issues are not yet relevant. “Our work within the SGC initiative has a major impact on the next generation of industrial drug development,” says Stefan Knapp. “Academic research and industry are working together here on an equal footing. This approach is a blueprint for further open science projects that support the rapid development of affordable drugs.”
Futher informations
EUbOPEN
Target-2035-Initiative
Structural Genomics Consortium (SGC)
About / Stefan Knappstudied chemistry at Philipps-Universität Marburg and the University of Illinois (USA) and earned his doctoral degree in protein crystallography at the Karolinska Institutet in Stockholm in 1996. From 1999 to 2004, he was a researcher at Pharmacia Corporation (a Swedish company that is now part of Pfizer Inc.). Knapp then worked at the University of Oxford, from 2008 to 2015 as Professor of Structural Biology, and from 2012 also as Director for Chemical Biology at the Target Discovery Institute. In 2015, Knapp joined Goethe University Frankfurt and the Buchmann Institute for Molecular Life Sciences (BMLS) as Professor of Pharmaceutical Chemistry.
Knapp@pharmchem.uni-frankfurt.de
The author / Dr. Benedikt Vogel, born in 1964 in Lucerne/Switzerland, works from Berlin as a freelance science journalist specializing in physics, energy and medicine. He also advises universities, associations and authorities on strategic questions related to communication.
