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Assays and Inhibitors for Jumonjic Domain-Containing Histone Demethylases As Epigenetic Regulators

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Assays and Inhibitors for Jumonjic Domain-Containing Histone Demethylases As Epigenetic Regulators Assays and Inhibitors for JumonjiC Domain-Containing Histone Demethylases as Epigenetic Regulators Martin Roatsch Assays and Inhibitors for JumonjiC Domain-Containing Histone Demethylases as Epigenetic Regulators Inauguraldissertation zur Erlangung des akademischen Grades eines Doctor rerum naturalium (Dr. rer. nat.) der Fakult¨atf¨urChemie und Pharmazie der Albert-Ludwigs-Universit¨atFreiburg vorgelegt von Martin Roatsch geboren in Berlin, Deutschland 2016 Eidesstattliche Versicherung gem¨aß x7, Absatz 1, Satz 3, Nr. 8 der Promotionsordnung der Albert-Ludwigs-Universit¨atf¨urdie Fakult¨atf¨urChemie und Pharmazie 1. Bei der eingereichten Dissertation zu dem Thema Assays and Inhibitors for JumonjiC Domain-Containing Histone Demethylases as Epigenetic " Regulators\ handelt es sich um meine eigenst¨andigerbrachte Leistung. 2. Ich habe nur die angegebenen Quellen und Hilfsmittel benutzt und mich keiner unzul¨assigen Hilfe Dritter bedient. Insbesondere habe ich w¨ortlich oder sinngem¨aßaus anderen Werken ¨ubernommene Inhalte als solche kenntlich gemacht. 3. Die Dissertation oder Teile davon habe ich bislang nicht an einer Hochschule des In- oder Auslands als Bestandteil einer Pr¨ufungs-oder Qualifikationsleistung vorgelegt. 4. Die Richtigkeit der vorstehenden Erkl¨arungen best¨atigeich. 5. Die Bedeutung der eidesstattlichen Versicherung und die strafrechtlichen Folgen einer unrichtigen oder unvollst¨andigeneidesstattlichen Versicherung sind mir bekannt. Ich versichere an Eides statt, dass ich nach bestem Wissen die reine Wahrheit erkl¨artund nichts ver- schwiegen habe. Freiburg i. Br., 2. Juni 2016 Unterschrift Dekan der Fakult¨at: Prof. Dr. Manfred Jung Vorsitzender des Promotionsausschusses: Prof. Dr. Stefan Weber Referent: Prof. Dr. Manfred Jung Koreferent: Prof. Dr. Bernhard Breit Datum der m¨undlichen Pr¨ufung: 29. Juni 2016 Datum der Verpflichtung: 7. Juli 2016 Zusammenfassung JumonjiC-Dom¨anen-enthaltende Histon-Demethylasen (JMJC-Demethylasen) sind epigeneti- sche Radierer\-Enzyme, welche Methylgruppen von den "-Aminogruppen der Histon-Lysin- " reste in einem oxidativen und Eisen(II)-/α-Ketoglutarat-abh¨angigenMechanismus entfernen. Ihre Beteiligung an einer Vielzahl von Krankheiten, insbesondere Krebs, wurde beschrieben. Eine Screening-Plattform mit zwei orthogonalen In-vitro-Enzymaktivit¨ats-Messsystemen wurde f¨urJMJD2A (KDM4A) etabliert und die LANCEUltra-Methode auf die verwandten Demethylasen JARID1A (KDM5A) und JMJD3 (KDM6B) ¨ubertragen. Mithilfe dieser Plattform wurden mehrere Screening-Kampagnen f¨urHemmstoff-Leitstrukturen durchgef¨uhrt, basierend sowohl auf rationalem Design, fragment-basiertem und analogie-basiertem Screening, virtuellem Screening sowie der Untersuchung fokussierter Substanz-Bibliotheken. Hiermit konnten mehrere neue Leitstrukturen f¨urHemmstoffe identifiziert und iterativ in R¨uckkopplung mit biologischen Testungen optimiert werden. Dies gilt f¨ur Naturstoffe und synthetische Derivative der Tropolon-Klasse sowie fragment-artige Tetrazolylhydrazide mit bemerkenswerter KDM4A-Selektivit¨at. Mithilfe von virtuellem Screening wurden Aminopyrimidylpyridine mit submikromolarer Potenz und KDM4- und KDM5-Subfamilien- Selektivit¨atentdeckt. Eine Syntheseplattform f¨urAnaloga und Prodrugs wurde etabliert und diese Prodrugs hemmten das Zellwachstum von KYSE-150-Speiser¨ohrenkrebs-Zellen.Ein Hydroxamat-basierter Hemmstoff von Zink-abh¨angigenHiston-Desacetylasen wurde so modi- fiziert, dass seine Enzymklassen-Selektivit¨atf¨urJMJC-Demethylasen umgekehrt wurde. Die Struktur-Aktitiv¨ats-Beziehungen wurden eingehend untersucht und Derivate hemmten das Zellwachstum von Leuk¨amie-Zellenin JMJC-Demethylase-abh¨angigerArt. Klinisch einge- setzte Eisen-Chelatoren wie Deferasirox und neue synthetisierte Analoga hemmten potent die Demethylasen sowohl in vitro als auch in vivo in einer Reihe von Speiser¨ohrenkrebs-Zellenund direkte Effekte auf die zellul¨areHiston-Methylierung konnten nachgewiesen werden. Diese neuen Leitstrukturen stellen wertvolle Werkzeug-Verbindungen dar, mit denen die physiologische Rolle der JMJC-Demethylasen untersucht werden kann, und dienen als Ausgangspunkt f¨urdie Entwicklung neuartiger Therapiekandidaten. i Summary JumonjiC domain-containing histone demethylases (JMJC demethylases) are epigenetic \eraser" enzymes that oxidatively remove methyl marks from the "-amino groups of histone lysine residues in an iron(II)- and 2-oxoglutarate-dependent mechanism. Their involvement in a number of diseases and, in particular, cancer has been recognized. A screening platform using two orthogonal in vitro enzyme activity assays has been estab- lished for JMJD2A (KDM4A) and the LANCEUltra system also expanded to be used with related demethylases JARID1A (KDM5A) and JMJD3 (KDM6B). This platform has been used in several lead structure screening campaigns using fragment-based drug discovery, ratio- nal design, virtual screening, and analogy-based and focused library screening. Thus, several novel inhibitor lead structures were discovered and optimized iteratively in feedback with biological testing. This includes a natural product and its analogs of the tropolone class and fragment-like tetrazolyl hydrazides with remarkable KDM4A selectiv- ity. Virtual screening identified aminopyrimidylpyridines with sub-micromolar potency and KDM4 and KDM5 subfamily selectivity. A synthetic platform towards analogs and pro- drugs was established and prodrugs inhibited cell proliferation of KYSE-150 esophageal cancer cells. A hydroxamate-based inhibitor of zinc-dependent HDACs could be modified and its enzyme class selectivity reverted towards JMJC demethylases. Its structure-activity relation- ship was studied extensively and derivatives inhibited cell proliferation of a leukemia cell line in a JMJC demethylase-dependent manner. Clinically used iron chelators like deferasirox and novel synthetic analogs potently inhibited demethylases in vitro and in vivo in a broad range of esophageal cancer cells with on-target effects on cellular histone methylation levels. These novel lead structures are valuable tool compounds to study the physiological role of JMJC demethylases and provide starting points for therapeutic candidates. ii The experimental parts of this research project as well as the production of the present thesis were undertaken between March 2012 and May 2016 in the group of Prof. Dr. Manfred Jung at the Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg. I would like to express my gratitude to all the individuals who have made it possible for me to undertake this fascinating research project and who have made our time together so very rewarding. First and foremost to my supervisor Prof. Dr. Manfred Jung for inviting me into his group, sharing this interesting and compelling topic of our project with me, and his many useful hints and valuable techniques I was allowed to learn from him. I would also like to acknowledge the other members of my thesis advisory committee Prof. Dr. Bernhard Breit and Dr. Wolfgang H¨uttelfor their time and dedication and many inspiring discussions of this project. I am also grateful for the help I received from `Team Jumonji' Dr. Inga Hoffmann and Dr. Ludovica Morera, with whom I enjoyed a very fruitful collaboration over so many years and without whom this project would not have advanced so far. I would like to thank all present and former members of the Jung group: Bright Asamoah, Johannes Bacher, Tobias Borgmann, Teresa Burgahn, Dr. Alokta Chakrabarti, Julia Eib, Dr. Silviya Furdas, S¨oren Hammelmann, Mirjam Hau, Dr. Alexander Hauser, Daniel Herp, Eva-Maria Herrlinger, Dr. Kristina Keller, Andreas K¨urner,Laura M¨unninghoff,Dr. Benjamin Maurer, Daria Monaldi, Dr. Tobias Rumpf, Dr. Matthias Schiedel, Karin Schmidtkunz, Dr. Martin Schmitt, Johannes Schulz-Fincke, Johanna Senger, Roman Simon, Dr. Diana Stolfa, S¨orenSwyter, Dr. Tobias Wagner, Alexan- dra Walter, Sandra Wenzler, and Dr. Sarah Z¨ahringer.They have created a truly wonderful work atmosphere in and out of the lab, making it very worthwhile to achieve such riveting results together with such an enthusiastic team. I am also thankful to all thesis and intern students who chose to join the Jung group and who contributed to this project: Marina Auth, Paul Disse, Ahmed Hassan, Eva-Maria Herrlinger, Bj¨ornKlaiber, Juliane Mietz, Soma Mohammadamin, Nicole Steck, and Katharina Wolf. I am grateful to the Collaborative Research Center 992 `Medical Epigenetics' for funding of this project and to its integrated research training group. I have been allowed to meet many dedicated young scientists from different fields and benefit from their various expertises. This enthusiastic team of young students has supported me both in and outside of official meetings. iii In particular, I want to point out Dr. Theresa Ahrens, Dr. Inga Hoffmann, C. Felix Krombholz, and Dr. Xavier Lucas, who have become not only collaborators, but great friends. I am equally grateful for the support I received through scholarships from the Studienstiftung des deutschen Volkes both during my undergraduate as well as my doctoral studies and the many inspiring people from all walks of life I was allowed to meet. I am thankful to the group of Prof. Dr. Wolfgang Sippl (MLU Halle-Wittenberg) and in parti- cular Dr. Martin Pippel and Dr. Dina Robaa for their contributions in molecular docking and virtual screening, which have greatly advanced many aspects of this project. I would like to thank Dr. Henriette Franz and the entire team of Prof. Dr. Roland Sch¨ule (University
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