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Modular toolbox for therapeutic targeting of transcription factors

Applicant Kinter Jochen
Number 190369
Funding scheme Spark
Research institution Universität Basel
Institution of higher education University of Basel - BS
Main discipline Pharmacology, Pharmacy
Start/End 01.12.2019 - 31.03.2021
Approved amount 96'000.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Molecular Biology

Keywords (8)

ubiquitin; FSHD; PROTAC; degradation; Transcription factor; homeobox; aptamer; DUX4

Lay Summary (German)

Lead
Transkriptionsfaktoren sind Proteine, die die Genaktivität regulieren und somit fundamentale biologische Prozesse wie zum Beispiel Zellwachstum, Immunreaktion, Zelltod oder auch Gewebeentwicklung beeinflussen. Störungen solcher Genaktivierungsmuster können zu verschiedensten Krankheiten führen. Transkriptionsfaktoren sind daher attraktive Zielmoleküle um Medikamente zu entwickeln, die einer Fehlregulation entgegenwirken. Leider hat sich gezeigt, dass es sehr schwierig ist, kleinmolekulare Substanzen zu entwickeln, die die Funktion von Transkriptionsfaktoren spezifisch modulieren können.
Lay summary

Das Ziel dieses Projekts ist es eine neue Technologie zu entwickeln, die es erlaubt die Deregulierung von Transkriptionsfaktoren zu unterbinden. Dieses Ziel soll erreicht werden, indem mit der gezielten Entwicklung von chimären Molekülen der Abbau spezifischer Transkriptionsfaktoren induziert. Diese chimären Moleküle bestehen aus einem Nukleinsäurebestandteil und speziellen chemischen Modifikationen, die den zelleigenen Abbauapparat dazu bringt, den deregulierten Transkriptionsfaktor abzubauen.

Diese chimären Moleküle werden in einem modularen Verfahren synthetisiert, um eine möglichst flexible Gestaltung der Moleküle zu erreichen und somit eine grosse Vielzahl verschiedener Moleküle in biochemischen und zellulären Systemen zu testen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Dieses Projekt befasst sich mit dem unerfüllten medizinischen Bedarf an neuen Technologien, um der Deregulierung von Transkriptionsfaktoren in vielen Krankheiten entgegenzusteuern. Die Entwicklung dieser neuen Methode könnte die Grundlage für neue Medikamente sein, die Transkriptionsfaktoren regulieren und somit einen grossen medizinischen Patientennutzen haben.

Direct link to Lay Summary Last update: 28.11.2019

Responsible applicant and co-applicants

Collaboration

Group / person Country
Types of collaboration
Michael Kyba, University of Minnesota United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Abstract

Transcription factors are fundamental regulators of gene expression involved in many biological processes (i.e.cellular development, cell cycle progression, immune response, and cell death). Dysregulation of cellular gene expression is associated with numerous diseases, including cancer, autoimmunity, neurological disorders, diabetes, cardiovascular disease, and obesity to name a few. Therefore, transcription factors are attractive drug targets and potential drug candidates would have a high impact for patients. Pharmacologically targeting transcription factors is a key challenge in many disease areas, especially in cancer research. Early attempts targeting transcription factors directly with small molecules to prevent DNA-protein or protein-protein interaction failed. Due to the great efforts in the last years to develop new strategies with improved efficiency and therapeutic potential, the perception of transcription factors as undruggable targets changed. Nevertheless, transcription factors are still considered as difficult or as “not-yet druggable” underscoring the need of innovation and the development of new technologies to turn this class of proteins into druggable targets.A recent promising strategy to target proteins is the PROTAC (proteolysis targeting chimera) technology, which uses bifunctional molecules to link the target protein to the ubiquitin-proteosome machinery for degradation. Several small molecules targeting different E3 ubiquitin ligases are available or are under development. The broad use of this technology in standard research laboratories is limited by the availability of molecules binding selectively the protein of interest. Although methods like DNA-encoded chemical libraries screening potentially enable the identification of such molecules, these methods will not be easily accessible in a standard research environment.The goal of this proof of concept study is to establish a modular toolbox for constructing molecules for the targeted degradation of transcription factors. We employ the sequence specific binding activity of transcription factors by using oligonucleotides to target the transcription factor of interest. Using simple click chemistry degrading molecules can be covalently attached to the oligonucleotide. In vitro and in cellulo experiments will be performed to validate their capability to degrade the transcription factor of interest and to modulate its target genes. In a next step cell penetrating peptides will be added as third component to the modular system to enhance and guide cellular uptake. As result of the modular concept, this toolbox will be able to generate a large source of numerous variations of molecules targeting transcription factors for degradation. The modular toolbox is designed to allow the construction of new molecules in a simple way within a short time frame enabling standard research laboratories to study the concept of targeted proteolysis of their transcription factor of interest. By adding a delivery component like cell penetrating peptides as further module the generated new molecules may also have therapeutic potential for a variety of dieseases.
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