Selective Proteolysis of Activated Transcriptional Factor by NIR‐Responsive Palindromic DNA Thalidomide Conjugate Inhibits the Canonical Smad Pathway

Abstract

AbstractDysfunctional transcription factors that activate abnormal expressions of specific proteins are often associated with the progression of various diseases. Despite being attractive drug targets, the lack of druggable sites has dramatically hindered their drug development. The emergence of proteolysis targeting chimeras (PROTACs) has revitalized the drug development of many conventional hard‐to‐drug protein targets. Here, the use of a palindromic double‐strand DNA thalidomide conjugate (PASTE) to selectively bind and induce proteolysis of targeted activated transcription factor (PROTAF) is reported. The selective proteolysis of the dimerized phosphorylated receptor‐regulated Smad2/3 and inhibition of the canonical Smad pathway validates PASTE‐mediated PROTAF. Further aptamer‐guided active delivery of PASTE and near‐infrared light‐triggered PROTAF are demonstrated. Great potential in using PASTE for the selective degradation of the activated transcription factor is seen, providing a powerful tool for studying signaling pathways and developing precision medicines.