Synthese, in vitro und in vivo Evaluierung molekularer Sonden, PROTACs und PET-Tracern zur Adressierung der Proteinkinase Akt
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2022
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Abstract
Tumorerkrankungen stellen weltweit die zweithäufigste Todesursache dar und aufgrund der demographischen Entwicklung nimmt die Anzahl der Neuerkrankungen und Todesfälle stetig zu. Zur Adressierung der Proteinkinase Akt, ein hochrelevantes Protein in der Tumorentstehung, wurde für die präklinische Entwicklung die Hochskalierung eines kovalent-allosterischen Akt Inhibitor (CAAI) durchgeführt. Hiermit konnten in ersten Xenograft-Modellen vielversprechende Ergebnisse erhalten werden. Zur Optimierung der PK-Eigenschaften dieses CAAI wurde der chemische Raum erweitert. Die kleine fokussierte Substanzbibliothek auf Basis eines monozyklischen Pyridins lieferte neue Einblicke in die SAR der CAAIs. Dies ermöglichte das Design und die Synthese eines Akt-spezifischen Radioliganden, welcher in ersten in vivo Tiermodellen ein stabiles radioaktives Signal induzierte und durch weitere Optimierung zur Entwicklung eines PET-Tracers beitragen kann. Zur genaueren Analyse der Tumorbiologie von Akt wurden molekulare Sonden auf Basis der CAAIs entwickelt und in vitro etabliert. Als neuer innovativer Adressierungsansatz konnten erfolgreich die ersten drei Akt-spezifischen allosterischen PROTACs dargestellt werden, die einen Akt1-Abbau in Panc1-Zellen induzierten.
Tumor diseases represent the second leading cause of death worldwide and due to demographic trends the number of new cases and deaths is steadily increasing. To address the protein kinase Akt, a highly relevant protein in tumorigenesis, upscaling of a covalent-allosteric Akt inhibitor (CAAI) was performed for preclinical development. Promising results were obtained with this in initial xenograft models. To optimize the PK properties of this CAAI, the chemical space was expanded. The small focused compound library based on a monocyclic pyridine provided new insights into the SAR of CAAIs. This enabled the design and synthesis of an Akt-specific radioligand, which induced a stable radioactive signal in initial in vivo animal models and may contribute to the development of a PET tracer through further optimization. For a more detailed analysis of Akt tumor biology, molecular probes based on CAAIs were developed and established in vitro. As a new innovative targeting approach, the first three Akt-specific allosteric PROTACs were successfully displayed, which induced Akt1 degradation in Panc1 cells.
Tumor diseases represent the second leading cause of death worldwide and due to demographic trends the number of new cases and deaths is steadily increasing. To address the protein kinase Akt, a highly relevant protein in tumorigenesis, upscaling of a covalent-allosteric Akt inhibitor (CAAI) was performed for preclinical development. Promising results were obtained with this in initial xenograft models. To optimize the PK properties of this CAAI, the chemical space was expanded. The small focused compound library based on a monocyclic pyridine provided new insights into the SAR of CAAIs. This enabled the design and synthesis of an Akt-specific radioligand, which induced a stable radioactive signal in initial in vivo animal models and may contribute to the development of a PET tracer through further optimization. For a more detailed analysis of Akt tumor biology, molecular probes based on CAAIs were developed and established in vitro. As a new innovative targeting approach, the first three Akt-specific allosteric PROTACs were successfully displayed, which induced Akt1 degradation in Panc1 cells.
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Molekulare Sonden, PROTAC, PET-Tracer, Medizinalchemische Adressierung der Proteinkinase Akt