Verena Kunig was awarded a prestigious poster prize at the EFMC-ISMC & EFMC-YMCS congress 2020 for her disclosure of TEAD-YAP protein-protein interaction inhibitors. Congratulations!
A key step in the development of innovative drugs for the treatment of cancer is the identification of molecules that specifically intervene in the complex cellular processes of a degenerated cancer cell and thus improve our understanding of tumor biology. Verena Kunig from the Brunschweiger research group of the Faculty of Chemistry and Chemical Biology succeeded in using a DNA-encoded substance library (DEL) designed by her to identify molecules that inhibit a tumor-relevant, but for drug development very challenging mechanism. Her work was recently presented as a VIP article in the internationally renowned journal Angewandte Chemie.
A new class of molecules, which interferes with a cellular mechanism essential for many tumors, was found by Verena Kunig from the Brunschweiger group in an interdisciplinary and international research project. The molecules inhibit the binding of two transcription factors, whose interaction is used by tumor cells to induce important processes for cell growth, metastasis and the defense against tumor drugs. Her work was recently presented to an international audience as a VIP article in the renowned journal Angewandte Chemie. Only 5 % of all articles receive the status of VIP article, which is awarded to papers considered to be particularly important.
The DNA-encoded substance library was produced from a chemically stable hexathymidine ("hexT") adapter oligonucleotide using the TiDEC technology developed by the Brunschweiger group in Dortmund. It was designed by the first author using the Ugi multi-component reaction around indole structures to mimic the tryptophan amino acid side chain and thus to address protein-protein interactions. By subsequent copper-mediated alkyne-azide cycloaddition, a substance library consisting of thousands of DNA-encoded molecules could be generated. Selection experiments of the DNA-encoded substance library on the disease-relevant proteins MDM2 and TEAD4 led to the identification of a new MDM2-binder and to the discovery of an inhibitor of the protein-protein interaction of the transcription factor TEAD4 with the co-activator protein YAP. This protein-protein interaction is misregulated in many tumors, for example by mutations that lead to increased activation of the TEAD-YAP transcription complex. The class of molecules discovered by Verena Kunig has the potential to provide important impulses for research on this tumor-relevant mechanism.
The publication was developed in interdisciplinary and international collaboration with the working groups Rahnenführer and Fried from the Faculty of Statistics at the TU Dortmund University, who developed a new algorithm for drug discovery with DNA-encoded libraries (DELs); with the working group Dömling from the University of Groningen, who provided important support in the design of the DEL; with Department IV of the Max Planck Institute of Molecular Physiology (MPI) and the AstraZeneca-MPI Satellite Unit, who investigated the compounds in vitro; and with the Lead Discovery Center GmbH Dortmund (LDC), and the Ottmann working group from the University of Eindhoven, who investigated the molecules in tumor cells. The work was made possible in important parts by the Drug Discovery Hub Dortmund (DDHD).
We recently published a Digest Article in Tetrahedron Letters on recent advances in reaction development for DNA-encoded library synthesis. It gives the reader background information on the technical challenges in translating reaction methodology.
We are very grateful for most generous support by the Deutsche Forschungsgemeinschaft (DFG). The DFG will support a project to develop novel DNA-barcoding strategies that shall give access to encoded libraries covering unprecedented chemical space.
During a ceremony on January 15, 2020, Privatdozent Dr. Andreas Brunschweiger was awarded the Venia Legendi by the Dean of the Faculty of Chemistry and Chemical Biology, Professor Dr. Stefan Kast.
Dr. Andreas Brunschweiger studied pharmacy at the University of Kiel, received his doctorate at the University of Bonn in the group of Professor Christa Müller and did postdoctoral research in the group of Professor Jonathan Hall at the ETH Zurich before moving to the TU Dortmund University in 2013 to establish his own research at the TU Dortmund University in the field of DNA-encoded molecular libraries.
He was awarded the Venia Legendi of the Faculty of Chemistry and Chemical Biology by Professor Dr. Stefan Kast on January 15, 2020. In his inaugural lecture "Exploring heterogeneous systems for DNA-encoded library synthesis" Andreas Brunschweiger gave a short introduction to the manifold challenges but also opportunities in drug discovery and the technology of DNA-encoded molecular libraries. This novel technology can make important contributions to drug discovery in the future. Dr. Brunschweiger outlined the state of the art and described new strategies that his working group at the TU Dortmund University is developing for the design of DNA-encoded molecule libraries. These extend the spectrum of methods for the synthesis of DNA-encoded libraries and thus enable access to greater molecular diversity. The screening of an encoded molecular library produced by his working group enabled the identification of a substance class that intervenes in a tumor-relevant mechanism. Future fields of work in which his research group is engaged are the development of new coded molecule classes, the rational, diversity-oriented design of coded molecule libraries, the use of laboratory automation to accelerate method development, but also library synthesis, and finally the broad application of the molecule libraries to find new drugs on disease-relevant proteins. In these fields, his group works together with several working groups at the TU Dortmund University in an interdisciplinary way.
In a recently published article, Dr. Brunschweiger's group describes an extensive investigation of the chemical stability of DNA sequences. This enables chemists to select reactions for the synthesis of DNA-encoded molecule libraries used for drug screening. The work was published in the renowned journal Chemical Science and was especially appreciated as Inside Back Cover.
DNA-encoded molecule libraries have become a widely used technology for drug discovery in the pharmaceutical industry. The synthesis of these molecular libraries is still limited to very few reactions despite the very impressive progress published in recent years. A blank space in this technology is the investigation of the chemical stability of DNA sequences. In their article "Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions", published in the renowned journal Chemical Science, Marco Potowski and colleagues present a broad-based investigation of the chemical stability of DNA. The authors examined more than 50 metal ions and organic reagents for their compatibility with DNA. The results showed that surprisingly many of these metal ions and reagents hardly damaged DNA under rather mild reaction conditions. The results of this investigation allowed the selection of three reactions for the synthesis of DNA-encoded molecular libraries. It will enable chemists to select further reactions for DNA-encoded chemistry.
DNA-encoded molecule libraries have become a highly sought-after technology for drug discovery. The development of new synthesis methods for the production of these molecule libraries is technically very challenging due to the chemical instability of DNA. An interdisciplinary collaboration of the Brunschweiger group, Weberskirch and Raunser was able to develop a new approach for the production of DNA-encoded molecule libraries based on the encapsulation of catalysts in micelles. This work was recently published in the renowned Journal of the American Chemical Society.
The search for new active ingredients is a complex, high-risk undertaking. The coupling of drug-like molecules to DNA sequences, which act as barcodes of the molecules, enables the cost-effective production of very large libraries of such molecules and highly efficient testing for potential active ingredients. Up to now, the chemical instability of DNA has extremely limited the spectrum of methods for producing these molecule libraries. Therefore, a central challenge to further develop this exciting technology is the development of synthesis methods to produce a wide range of molecules in an encoded form.
In an interdisciplinary collaboration that could only be carried out in Dortmund in this form worldwide, scientists from the two working groups Brunschweiger and Weberskirch at the TU Dortmund University and the working group Raunser at the MPI Dortmund have demonstrated the application of an innovative catalyst class for the synthesis of DNA-labeled molecules. Polymers produced in Prof. Weberskirch's working group form nanometer-sized, three-dimensional structures, so-called oil-in-water micelles, in water and immobilize a catalyst in their hydrophobic core. This catalyst is thus inaccessibly encapsulated for the water-soluble DNA barcode. Dr. Brunschweiger's working group was able to demonstrate that in these nanoreactors small starting products coupled to DNA are selectively converted into desired target structures without DNA destruction. In the working group of Prof. Raunser, the reactions were examined by electron microscopic images. The principle of micellar catalysis shown here offers considerable potential for broad application not only in the synthesis of DNA-coded molecule libraries, but also for the selective modification of other biomacromolecules.
The research on micellar catalysis was recently presented to an international audience in the renowned Journal of the American Chemical Society.
"Micellar Brønsted Acid Mediated Synthesis of DNA-Tagged Heterocycles"
M. Klika Škopić, K. Götte, C. Gramse, M. Dieter, S. Pospich, S. Raunser, R. Weberskirch*, A. Brunschweiger, J. Am. Chem. Soc. 2019, 141, 26, 10546-10555.
The Brunschweiger group is one of three winners of the scientific competition "Forum Junge Spitzenforscher", which was organized by the Center for Entrepreneurship and Transfer (CET) of the TU Dortmund University. The group conducts research in the field of DNA-encoded molecular libraries that enable efficient drug discovery. It was awarded for its development of DNA coding strategies that allow a broad spectrum of chemical synthetic methods to be transferred into an encoded format.
The Center for Entrepreneurship and Transfer (CET) at the TU Dortmund University, in cooperation with the Stiftung Industrieforschung, has organized a competition to promote the transfer of innovative ideas on the topic of "transformation". This competition was aimed at all universities in the Ruhr region. The first three places were awarded €10,000 each. The Arbeitskreis Brunschweiger was awarded third place for its research in the field of DNA-coded chemistry, as this research has a high potential for commercial applications in the field of pharmaceutical research. The coding of small, drug-like molecules with DNA barcodes enables the production of very large numbers of such molecules and to screen them as complex mixtures highly efficiently for potential drug candidates. The Brunschweiger group develops molecule coding strategies that address a problem that has been unsatisfactorily solved so far, the small number of synthesis methods used to produce these molecule libraries. They thus make a broad spectrum of molecule classes accessible in an encoded format for screening for active substances.
The Society of German Chemists and the German Pharmaceutical Society awarded Dr. Andreas Brunschweiger, group leader in the Faculty of Chemistry and Chemical Biology, the renowned Innovation Prize in Medicinal/Pharmaceutical Chemistry at the conference "Frontiers in Medicinal Chemistry" in Würzburg on March 26, 2019.
The Innovation Prize was awarded to Dr. Brunschweiger in recognition of his pioneering work in the field of synthesis of DNA-encoded molecular libraries. DNA-encoded molecule libraries are a novel technology that connects drug-like molecules with synthetic DNA strands. The DNA strands serve as barcodes, so to speak, which identify the molecules beyond any doubt. DNA labeling of molecules allows scientists to generate extremely large databases of molecules and to test them for potential active ingredients using a simple, highly efficient and cost-effective test system. One problem is so far the very narrow spectrum of synthesis methods that can be used to produce these molecule libraries. The Brunschweiger working group has found strategies that allow the use of a variety of synthesis methods for the production of encoded molecule libraries. In addition, in a very successful interdisciplinary collaboration with the group of Prof. Weberskirch, innovative catalysts that do not damage DNA are being investigated for the synthesis of DNA-encoded molecules. Currently, novel DNA-encoded molecule libraries are being synthesized as prototypes for various projects and tested for active ingredients using a software for reading DNA barcodes developed in cooperation with the Faculty of Statistics at the TU Dortmund University.
Katharina Götte joins the group as Ph.D. student. Wellcome!
Joint research project of the Brunschweiger group with Merck KGaA
The research group of Andreas Brunschweiger and Merck agreed to collaborate in the field of DNA-encoded chemistry. The aim of this joint research project is the development of new synthesis strategies to encoded compound libraries.
Joint research project of the Brunschweiger group with Bayer AG.
The research group of Andreas Brunschweiger and Bayer AG collaborate in the field of DNA-encoded chemistry. The aim of this joint research project is the development of new synthesis strategies to encoded compound libraries.
At the "7th International Conference on Multicomponent Reactions and Related Chemistry" in Düsseldorf, the paper by Verena Kunig from Dr. Brunschweiger's working group entitled "Genetic tagging of the Ugi-four-component reaction" was awarded one of three poster prizes.
In collaboration with the research group of Alexander Dömling at the University of Groningen, Ms. Kunig has synthesized a DNA-encoded substance library consisting of several thousand molecules for the inhibition of disease-relevant protein-protein interactions (for example the cancer-relevant p53-Mdm2 interaction) using optimized Ugi four-component reaction conditions.
For her pioneering research in the field of DNA-encoded chemistry, Dr. Mateja Klika Škopić was awarded the prestigious Klaus Grohe Prize for Medical Chemistry at this year's Frontiers in Medicinal Chemistry conference of the joint Medical Chemistry Section of the German Chemical Society (GDCh) and the German Pharmaceutical Society (DPhG) in Jena.
The Klaus Grohe Prize for medicinal chemistry is awarded by the Klaus Grohe Foundation. The founder, Prof. Dr. Klaus Grohe, developed innovative medicines with great success during his professional career at Bayer AG and is, among other things, the inventor of the broad-spectrum antibiotic ciprofloxacin. In 2001, Klaus and Eva Grohe established the Klaus Grohe Foundation at the Society of German Chemists, which aims to encourage highly qualified young people to turn to the challenging interdisciplinary field of medicinal chemistry.
DNA-encoded molecule libraries are primarily used by the research-based pharmaceutical industry as a modern, highly efficient technology for the identification of active ingredients. The extremely limited spectrum of chemical-synthetic methods for the production of these molecular libraries is considered by researchers to be very disadvantageous.
Dr. Mateja Klika Škopić established the technology of DNA-encoded chemistry in the junior research group of Dr. Andreas Brunschweiger and received her PhD with distinction in December 2017 at the Faculty of Chemistry and Chemical Biology of TU Dortmund University. In particular, she succeeded in developing a fundamentally new approach to DNA-coded libraries. The methodology developed by Dr. Klika Škopić allows for the first time the use of a significantly broader spectrum of synthesis methods for the production of these molecular libraries. The methodology thus enables the production of new chemically very diverse molecule libraries that can be used to search for active ingredients for disease-relevant proteins. The method is trend-setting for the long-term further development of the technology of DNA-encoded chemistry and has the potential to make important contributions to drug discovery.
Our research in a short video (german):
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The campus of TU Dortmund University is located close to interstate junction Dortmund West, where the Sauerlandlinie A 45 (Frankfurt-Dortmund) crosses the Ruhrschnellweg B 1 / A 40. The best interstate exit to take from A 45 is "Dortmund-Eichlinghofen" (closer to Campus Süd), and from B 1 / A 40 "Dortmund-Dorstfeld" (closer to Campus Nord). Signs for the university are located at both exits. Also, there is a new exit before you pass over the B 1-bridge leading into Dortmund.
To get from Campus Nord to Campus Süd by car, there is the connection via Vogelpothsweg/Baroper Straße. We recommend you leave your car on one of the parking lots at Campus Nord and use the H-Bahn (suspended monorail system), which conveniently connects the two campuses.
TU Dortmund University has its own train station ("Dortmund Universität"). From there, suburban trains (S-Bahn) leave for Dortmund main station ("Dortmund Hauptbahnhof") and Düsseldorf main station via the "Düsseldorf Airport Train Station" (take S-Bahn number 1, which leaves every 20 or 30 minutes). The university is easily reached from Bochum, Essen, Mülheim an der Ruhr and Duisburg.
You can also take the bus or subway train from Dortmund city to the university: From Dortmund main station, you can take any train bound for the Station "Stadtgarten", usually lines U41, U45, U 47 and U49. At "Stadtgarten" you switch trains and get on line U42 towards "Hombruch". Look out for the Station "An der Palmweide". From the bus stop just across the road, busses bound for TU Dortmund University leave every ten minutes (445, 447 and 462). Another option is to take the subway routes U41, U45, U47 and U49 from Dortmund main station to the stop "Dortmund Kampstraße". From there, take U43 or U44 to the stop "Dortmund Wittener Straße". Switch to bus line 447 and get off at "Dortmund Universität S".
The H-Bahn is one of the hallmarks of TU Dortmund University. There are two stations on Campus Nord. One ("Dortmund Universität S") is directly located at the suburban train stop, which connects the university directly with the city of Dortmund and the rest of the Ruhr Area. Also from this station, there are connections to the "Technologiepark" and (via Campus Süd) Eichlinghofen. The other station is located at the dining hall at Campus Nord and offers a direct connection to Campus Süd every five minutes.
The AirportExpress is a fast and convenient means of transport from Dortmund Airport (DTM) to Dortmund Central Station, taking you there in little more than 20 minutes. From Dortmund Central Station, you can continue to the university campus by interurban railway (S-Bahn). A larger range of international flight connections is offered at Düsseldorf Airport (DUS), which is about 60 kilometres away and can be directly reached by S-Bahn from the university station.
The facilities of TU Dortmund University are spread over two campuses, the larger Campus North and the smaller Campus South. Additionally, some areas of the university are located in the adjacent "Technologiepark".