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Modular toolbox for therapeutic targeting of transcription factors
Third-party funded project
Project title Modular toolbox for therapeutic targeting of transcription factors
Principal Investigator(s) Kinter, Jochen
Organisation / Research unit Departement Biomedizin / Neuromuscular Research (Sinnreich)
Project start 01.12.2019
Probable end 31.03.2021
Status Completed
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.

Financed by Swiss National Science Foundation (SNSF)
   

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