Abstract: Transcription factors (TFs) represent a major class of therapeutic targets for the treatment of human diseases including cancer. Although the biological function and even crystal structure of many TFs have been clearly elucidated, there is still no viable approach to target the majority of TFs, thus rendering them undruggable for decades. PROTACs (PROteolysis TArgeting Chimeras) have emerged as a powerful tool for the pharmaceutical development since the effect of PROTACs largely relies on engineered protein-protein interaction to aid the degradation of targets by the ubiquitin-proteasome system (UPS). The present disclosure provides a DNA-PROTAC platform for targeted degraders of individual TFs of interest. These DNA based Transcription Factor targetting PROTACS (or “TF-PROTACS”) may provide specificity to TF degradation based on the conserved DNA-binding motifs of respective TFs.

Abstract: PROTACs (PROteolysis TArgeting Chimeras) are an emerging class of promising therapeutic modalities that degrade intracellular protein targets by hijacking the cellular ubiquitin-proteasome system. However, potential toxicity of PROTACs in normal cells due to off-tissue on-target degradation effect limits their clinical applications. Precise control of PROTAC's on-target degradation activity in a tissue selective manner could minimize potential toxicity/side-effects. To this end, we developed a cancer cell selective delivery strategy for PROTACs by conjugating a folate group to ubqiquitin recruitment moiety to achieve targeted degradation of proteins of interest (POIs) in cancer cells versus normal cells. We show that our folate-PROTACs, including BRD PROTAC (Folate-ARV-771), MEK PROTAC (Folate-MS432) and ALK PROTAC (Folate-MS99, Folate-S2-MS4048) are capable of degrading BRDs, MEKs and ALK, respectively, in a folate receptor-dependent manner.