Targeting Undruggable Transcription Factors with PROTACs: Advances and Perspectives

Dysregulation of transcription factors has been implicated in a variety of human diseases. However, these proteins have traditionally been regarded as undruggable and only a handful of them have been successfully targeted by conventional small molecules. Moreover, the development of intrinsic and acquired resistance has hampered the clinical use of these agents. Over the past years, proteolysis-targeting chimeras (PROTACs) have shown great promise because of their potential for overcoming drug resistance and their ability to target previously undruggable proteins. Indeed, several small molecule-based PROTACs have demonstrated superior efficacy in therapy-resistant metastatic cancers. Nevertheless, it remains challenging to identify ligands for the majority of transcription factors. Given that transcription factors recognize short DNA motifs in a sequence-specific manner, multiple novel approaches exploit DNA motifs as warheads in PROTAC design for the degradation of aberrant transcription factors. These PROTACs pave the way for targeting undruggable transcription factors with potential therapeutic benefits.