OligoTRAFTACs: A generalizable method for transcription factor degradation.

Dysregulated transcription factors (TFs) that rewire gene expression circuitry are frequently identified as key players in disease. Although several TFs have been drugged with small molecules, the majority of oncogenic TFs are not currently pharmaceutically tractable due to their paucity of ligandable pockets. The first generation of transcription factor targeting chimeras (TRAFTACs) was developed to target TFs for proteasomal degradation by exploiting their DNA binding ability.

Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation.

With the discovery of PROteolysis TArgeting Chimeras (PROTACs) twenty years ago, targeted protein degradation (TPD) has changed the landscape of drug development. PROTACs have evolved from cell-impermeable peptide-small molecule chimeras to orally bioavailable clinical candidate drugs that degrade oncogenic proteins in humans. As we move into the third decade of TPD, the pace of discovery will only accelerate.