Antitumor Effect of Anti‐c‐Myc Aptamer‐Based PROTAC for Degradation of the c‐Myc Protein

Abstract Targeting “undruggable” targets with intrinsically disordered structures is of great significance for the treatment of disease. The transcription factor c‐Myc controls global gene expression and is an attractive therapeutic target for multiple types of cancers. However, due to the lack of defined ligand binding pockets, targeted c‐Myc have thus far been unsuccessful. Herein, to address the dilemma of lacking ligands, an efficient and high throughput aptamer screening strategy is established, named polystyrene microwell plate‐based systematic evolution of ligands by exponential enrichment (microwell‐SELEX), and identify the specific aptamer (MA9C1) against c‐Myc. The multifunctional aptamer‐based Proteolysis Targeting Chimeras (PROTAC) for proteolysis of the c‐Myc (ProMyc) is developed using the aptamer MA9C1 as the ligand. ProMyc not only significantly degrades c‐Myc by the ubiquitin‐proteasome system, but also reduces the Max protein, synergistically inhibiting c‐Myc transcriptional activity. Combination of the artificial cyclization and anti‐PD‐L1 aptamer (PA1)‐based delivery system, circular PA1‐ProMyc chimeras achieve tumor regression in the xenograft tumor model, laying a solid foundation for the development of efficacious c‐Myc degrader for the clinic. Therefore, this aptamer‐based degrader provides an invaluable potential degrader in drug discovery and anti‐tumor therapy, offering a promising degrader to overcome the challenge of targeting intractable targets.