|Titel:||Discovery and target identification of small molecule autophagy inhibitors|
|Zusammenfassung:||Pharmacologically active substances have been applied in medicine for at least 5300 years.Ever since, mankind has tried to enlarge the assortment of bio-active substances, in order to fight diseases and ultimately maintain health and quality of life. For thousands of years, but especially in the last century, drug discovery has been the scientific key driver for the progression of medicine. One process that attracts notable attention due to its high potential for the development of new drugs is autophagy. Autophagy is a catabolic process which plays a crucial role in the development, differentiation, homeostasis and survival of cells. It mediates the degradation of cellular components especially under conditions such as starvation, and the misregulation of autophagy is implicated in various diseases, ranging from cancer to microbial infections and neurodegenerative diseases. Small organic molecules still account for 90% of today’s pharmaceuticals and drug-like modulators of biological processes have proven to be valuable reagents and tools for chemical biology. However, to date only a few modulators of autophagy have been reported. Therefore the goal of this work was to identify and characterize new autophagy inhibitors. A cell-based assay was performed to identify inhibitors of autophagic flux. Based on hits from the cellular assay compound libraries were synthesized to provide information regarding structure-activity relationships. The identification of the targets of the inhibitors was achieved through affinity chromatography, mechanistic reasoning and the process of elimination. The examination of the targets’ roles in autophagy enlarged our understanding of the autophagic process and allowed us to evaluate their potential as new drug targets. Ultimately, the identified and characterized novel chemotypes for autophagy inhibition provide valuable tools to study their target protein’s function as well as the autophagic process more precisely. They can furthermore provide promising starting points for drug discovery focusing on cancer.|
|Enthalten in den Sammlungen:||Max-Planck-Institut für molekulare Physiologie|
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|Dissertation_Robke.pdf||DNB||55.56 MB||Adobe PDF||Öffnen/Anzeigen|
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