OligoTRAFTACs: A generalizable method for transcription factor degradation

Area of Science:

• Molecular Biology
• Drug Discovery
• Genetics

Background:

• Dysregulated transcription factors (TFs) are key drivers of disease but are often undruggable due to lack of ligandable pockets.
• Current therapeutic strategies struggle to target many oncogenic TFs effectively.
• Transcription factor targeting chimeras (TRAFTACs) offer a potential solution by hijacking cellular degradation machinery.

Purpose of the Study:

• To develop a second-generation TRAFTAC platform, termed oligoTRAFTACs, for targeted proteasomal degradation of transcription factors.
• To demonstrate the efficacy of oligoTRAFTACs against oncogenic transcription factors c-Myc and brachyury.
• To validate the in vitro and in vivo activity of oligoTRAFTACs.

Main Methods:

• Design and synthesis of oligoTRAFTACs, comprising a TF-binding oligonucleotide and an E3 ligase-recruiting ligand.
• Assessment of TF degradation in cancer cell lines, including chordoma models.
• In vivo validation of oligoTRAFTAC activity using zebrafish models.

Main Results:

• Successful development of oligoTRAFTACs, a second-generation TRAFTAC technology.
• Demonstrated degradation of oncogenic transcription factors c-Myc and brachyury by oligoTRAFTACs.
• Confirmed oligoTRAFTAC efficacy in chordoma cell lines and in vivo in zebrafish.

Conclusions:

• OligoTRAFTACs represent a versatile and generalizable platform for targeting previously undruggable transcription factors.
• This approach enables the degradation of oncogenic TFs via the proteasomal pathway.
• OligoTRAFTACs hold promise for developing new therapeutics against diseases driven by transcription factor dysregulation.