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Morphological Profiling of Small Molecules for Mode-Of-Action Studies Using the Cell Painting Assay

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Morphological Profiling of Small Molecules for Mode-Of-Action Studies Using the Cell Painting Assay Morphological Profiling of Small Molecules for Mode-of-Action Studies using the Cell Painting Assay Dissertation zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) der Fakultät für Chemie und Chemische Biologie der Technischen Universität Dortmund vorgelegt von M.Sc. Tabea Schneidewind geboren am 22.09.1990 in Steinheim, Deutschland Dortmund, 15.03.2021 Die vorliegende Arbeit wurde im Zeitraum von November 2016 bis März 2021 unter der Anleitung von Prof. Dr. Dr. h.c. Herbert Waldmann und Dr. Slava Ziegler an der Fakultät für Chemie und Chemische Biologie der Technischen Universität Dortmund und dem Max- Planck-Institut für molekulare Physiologie in Dortmund angefertigt. 1. Gutachter: Prof. Dr. Dr. h.c. Herbert Waldmann 2. Gutachter: Dr. Leif Dehmelt Publication list: T. Schneidewind, S. Kapoor, G. Garivet, G. Karageorgis, R. Narayan, G. Vendrell-Navarro, A. P. Antonchick, S. Ziegler, H. Waldmann, “The Pseudo Natural Product Myokinasib is a Myosin Light Chain Kinase 1 Inhibitor with Unprecedented Chemotype”, Cell Chem. Biol. 2019, 26, 512-523. A. Friese, S. Kapoor, T. Schneidewind, S. R. Vidadala, J. Sardana, A. Brause, T. Förster, M. Bischoff, J. Wagner, P. Janning, S. Ziegler, H. Waldmann, “Chemical Genetics Reveals a Role of dCTP Pyrophosphatase 1 in Wnt Signaling”, Angew. Chem. 2019, 131, 13143- 13147. J. Schulte-Zweckel, T. Schneidewind, J. L. Abad, A. Brockmeyer, P. Janning, G. Triola, “Azide-tagged sphingolipids for the proteome-wide identification of C16-ceramide-binding proteins”, Chem. Commun. 2018, 54, 13742-13745. Results presented in this thesis contributed to the following publications: T. Schneidewind, A. Brause, S. Sievers, A. Pahl, M. G. Sankar, M. Winzker, P. Janning, K. Kumar, S. Ziegler, H. Waldmann, "Combined morphological and proteome profiling reveals target-independent impairment of cholesterol homeostasis”, Cell Chem. Biol. 2020, in revision. T. Schneidewind, A. Brause, A. Pahl, A. Burhop, T. Mejuch, S. Sievers, H. Waldmann, S. Ziegler, "Morphological profiling identifies a common mode of action for small molecules with different targets”, ChemBioChem 2020, 21, 1-12. Acknowledgements I am very grateful for the past years as they made me grow as a scientist but also as a person in many ways. I would like to thank all people who contributed to my development. It was a very exciting but also demanding time that I will never forget. First and foremost, I would like to thank Prof. Dr. Dr. h.c. Herbert Waldmann for giving me the opportunity to join his research group with all the inspiring projects that I worked on. I highly appreciate the continuous access to outstanding equipment and really enjoyed the great working atmosphere, encouraging an independent way of work. I am still impressed by his scientific knowledge and his true passion for science and would like to thank him for his patient guidance and support. I would like to express my gratitude to Dr. Leif Dehmelt for taking the time and being my second examiner. My deepest gratitude goes to Dr. Slava Ziegler, my co-supervisor and group leader, for her constant guidance, support and valuable input that contributed to the success of my projects. She always had an open ear and helped with words and deeds if necessary. I also highly appreciate her encouragement to join workshops and seminars to broaden my mind in relation to scientific research but also to develop my soft skills. Furthermore, I would like to thank her for taking the time to proofread my thesis. My special thanks go to Alexandra Brause, who worked together with me after finishing her trainee. She is really talented and was extremely dedicated to contribute with her own ideas and scientific work to push my projects forward. She really was a great support and assistance, not only in the lab but also as a friend. I would like to thank the mass spectrometry facility, especially Dr. Petra Janning, Andreas Brockmeyer, Malte Metz and Jens Warmers for labelling and measuring my samples and analyzing the data. I really appreciate the constructive discussions and feedback regarding the experimental set up and data analysis. I would particularly like to thank the team of the Compound Management and Screening Center in Dortmund for support in terms of compound handling, stability, purity and screening, especially Dr. Sonja Sievers, Dr. Axel Pahl and Dr. Claude Ostermann. Sonja Sievers and Axel Pahl did an excellent job in setting up and performing the Cell Painting Assay as well as processing and analyzing the data. I am deeply grateful that they shared their knowledge and expertise, for valuable discussions, additional screenings, computational data and help in all kinds of analysis issues. I would also like to thank Annina Burhop, Dr. Tom Mejuch and Dr. Muthukumar G. Sankar for the synthesis of the uncharacterized small molecules presented in this thesis and Prof. Adam Nelson for fruitful discussions. I would like to express my gratitude to the administration of the Technical University Dortmund and for the variety of offered seminars and workshops. In addition, I gratefully acknowledge the administration and central facilities of the Max Planck Institute of Molecular Physiology. At this point I would also like to thank Brigitte Rose for her constant help and support in administrative issues. Furthermore, I am grateful and really appreciate the great work of the Max Planck PhDnet. I would like to thank in particular, Dr. Philine Hagel, Dr. Michael Winzker, Dr. Katrin Estel, Annina Burhop, Elisabeth Hennes, Birte Weyers, Georg Niggemeyer, Pascal Lill, Hans Seidel and Davide Tamborrini. At this point I would also like to thank the Students’ Chapter Dortmund of the International Chemical Biology Society (ICBS) for scientific exchange and discussions. I really enjoyed being a part of these organizations. Moreover, I highly appreciate the excellent working atmosphere, scientific discussions, summer BBQs and social events within this large international and highly collegial team of scientists. Especially I would like to thank Dr. Lea Kremer, Alexandra Brause, Annina Burhop, Jana Flegel, Dr. Nadine Kaiser, Dr. Elena Reckzeh, Elisabeth Hennes, Julian Wilke, Lara Dötsch, Aylin Binici, Jens Warmers and Beate Schölermann. Last but not least, I am deeply grateful for the emotional support from my family, my partner and friends. Their continuous encouragement and motivation throughout my PhD helped me to stay on track and focus on my scientific as well as personal goals. Thank you. TABLE OF CONTENTS 1 ABSTRACT ......................................................................................................................... 1 2 KURZZUSAMMENFASSUNG............................................................................................ 3 3 INTRODUCTION ................................................................................................................ 5 3.1 Chemical Biology......................................................................................................... 5 3.1.1 Classical versus chemical genetic approaches................................................... 5 3.1.2 Reverse chemical genetics .................................................................................. 6 3.1.3 Forward chemical genetics .................................................................................. 7 3.2 Bioactivity profiling of small molecules ....................................................................... 9 3.2.1 Gene expression profiling .................................................................................... 9 3.2.2 Genomics ........................................................................................................... 10 3.2.3 Transcriptomics .................................................................................................. 11 3.2.4 Proteomics ......................................................................................................... 12 3.2.5 Morphological profiling ....................................................................................... 12 3.2.6 Data analysis and application of morphological profiling .................................. 14 3.2.7 Cell Painting Assay ............................................................................................ 18 4 AIM OF THE THESIS ....................................................................................................... 23 5 MATERIAL AND METHODS ............................................................................................ 25 5.1 Materials .................................................................................................................... 25 5.1.1 Chemicals and reagents .................................................................................... 25 5.1.2 Buffers and media .............................................................................................. 27 5.1.3 Antibodies .......................................................................................................... 27 5.1.4 Plasmids ............................................................................................................. 28 5.1.5 Cell lines ............................................................................................................. 28 5.1.6 Cell culture media and supplements ................................................................. 29 5.1.7 Kits ....................................................................................................................
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