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

Author:

He Shipeng1,Fang Yuxin2,Zhu Yaojin1,Ma Ziyang2,Dong Guoqiang2,Sheng Chunquan2ORCID

Affiliation:

1. Institute of Translational Medicine Shanghai University 99 Shangda Road Shanghai 200444 P. R. China

2. Center for Basic Research and Innovation of Medicine and Pharmacy (MOE) School of Pharmacy Second Military Medical University (Naval Medical University) 325 Guohe Road Shanghai 200433 P. R. China

Abstract

AbstractProteolysis‐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.

Funder

National Natural Science Foundation of China

National Key Research and Development Program of China

Publisher

Wiley

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