Drugtamer‐PROTAC Conjugation Strategy for Targeted PROTAC Delivery and Synergistic Antitumor Therapy

Abstract

Proteolysis‐targeting chimeras (PROTACs) have emerged as a promising strategy for targeted protein degradation and drug discovery. To overcome the inherent limitations of conventional PROTACs, an innovative drugtamer‐PROTAC conjugation approach is developed to enhance tumor targeting and antitumor potency. Specifically, a smart prodrug is designed by conjugating “drugtamer” to a nicotinamide phosphoribosyltransferase (NAMPT) PROTAC using a tumor microenvironment responsible linker. The “drugtamer” consists of fluorouridine nucleotide and DNA‐like oligomer. Compared to NAMPT PROTAC and the combination of PROTAC + fluorouracil, the designed prodrug AS‐2F‐NP demonstrates superior tumor targeting, efficient cellular uptake, improved in vivo potency and reduced side effects. This study provides a promising strategy for the precise delivery of PROTAC and synergistic antitumor agents.

Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions

“…161 The drugtamer-PROTAC conjugation strategy holds promise for the targeted delivery of PROTACs with synergistic drugs for NAMPTbased therapy. 162 Finally, the in vivo active LYP-8 demonstrates promise as a potential novel cancer therapy. 163 Together, these advances highlight the immense potential of PROTAC technology for effective and targeted NAMPT degradation in cancer treatment.…”

“…Research has further expanded into next-generation strategies such as semiconducting polymer NanoPROTACs, which not only degrade NAMPT but also suppress myeloid-derived suppressive cells and promote antitumor immunity . The drugtamer-PROTAC conjugation strategy holds promise for the targeted delivery of PROTACs with synergistic drugs for NAMPT-based therapy . Finally, the in vivo active LYP-8 demonstrates promise as a potential novel cancer therapy .…”