GLUTs-Facilitated Targeting BRD4 Degradation in Breast Cancer through Carbohydrate-Conjugated PROTACs
Proteolysis-targeting chimeras (PROTACs) are an emerging class of therapeutic agents for anticancer treatments by degrading intracellular proteins via the ubiquitin-proteasome system. However, clinical applications of PROTACs are limited by the undesired normal cell toxicity resulting from off-tissue on-target degradation. To address this, we developed a tumor-selective delivery strategy by conjugating carbohydrate moieties to the ligand of the VHL E3 ubiquitin ligase, which enables targeted degradation of proteins of interest in GLUTs-overexpressing cancer cells. We designed and synthesized two series of carbohydrate and BRD PROTAC (ARV-771) conjugates. These compounds degraded BRD4 in a concentration- and time-dependent manner, with <b>NG-2</b> showing the highest degradation efficiency. Moreover, <b>NG-2</b>'s degradation effect was GLUTs- and proteasome-dependent, with selective targeting and effective degradation in high GLUTs-expressing cells. Furthermore, <b>NG-2</b> inhibited tumor growth without significant toxicity in vivo. These findings demonstrate the potential of carbohydrate-PROTAC as a targeted cancer therapy with minimized off-tissue on-target degradation.
Authors
- Yijie Xiao
- Xi Tang
- Yi He (ORCID: https://orcid.org/0000-0002-5562-4190)
- Yue Wei (ORCID: https://orcid.org/0000-0002-1673-2826)
- Shenyou Nie (ORCID: https://orcid.org/0000-0002-7396-8114)
- Linfeng Li (ORCID: https://orcid.org/0000-0001-6185-4999)
- Xing Wang (ORCID: https://orcid.org/0000-0002-5274-5659)
- Ke Zhang (ORCID: https://orcid.org/0000-0002-0149-3543)
- Yueying Li (ORCID: https://orcid.org/0000-0003-4126-0522)
- Jia Zheng (ORCID: https://orcid.org/0000-0003-1669-1566)
- Dan Ni (ORCID: https://orcid.org/0000-0002-8893-0282)
- Zufeng Guo (ORCID: https://orcid.org/0000-0002-4370-9445)
- Yunyun Gao (ORCID: https://orcid.org/0000-0003-3246-2536)
Institutions
- Ministry of Internal Affairs of the Republic of Tajikistan (TJ)
- Target (United States) (US)
- Dalian Medical University (CN)
- Second Affiliated Hospital of Chongqing Medical University (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00468
- Citations
- 10
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- National Natural Science Foundation of China
- Chongqing Science and Technology Commission
- Chongqing Medical University
- Natural Science Foundation of Chongqing
- Chongqing Municipal Education Commission