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OligoTRAFTACs: A generalizable method for transcription factor degradation

Kusal T. G. Samarasinghe, Elvira An, Miriam A. Genuth, Ling Chu, Scott A. Holley and Craig M. Crews

Many diseases, including cancer, stem from aberrant activation or overexpression of proteins that rewire multiple oncogenic signalling pathways. Although proteins with catalytic activity have been successfully drugged, a majority of 乐天堂app下载 proteome remains intractable due to 乐天堂app下载 lack of ligandable pockets.

Two decades of continuous efforts to develop heterobifunctional degraders have brought targeted protein degradation to an exciting and promising era of next-generation medicines. TPD by PROteolysis TArgeting Chimeras (PROTACs) has significantly grown over 乐天堂app下载 last twenty years.

Despite 乐天堂app下载 significant advancement in 乐天堂app下载 field, targeting key regulators of gene expression, mainly transcription factors (TFs), has been a major challenge. To address this matter, we have developed an alternative approach to target TFs for proteasomal degradation.

In this study, we have demonstrated 乐天堂app下载 utility of TF-binding short DNA sequences in heterobifunctional degrader design. More specifically, oligonucleotide-based TRAnscription Factor Targeting Chimera (oligoTRAFTACs), composed with a TF-binding DNA sequence and an E3- ligase binding small molecule ligand, successfully demonstrated c-MYC and brachyury degradation in both cells and animal model.

Our proof-of-principle study showcases that TF-binding DNA elements can be used in heterobifunctional degrader development towards previously intractable oncogenic transcription factors.