2. Academic Validation
  3. GLUTs-Facilitated Targeting BRD4 Degradation in Breast Cancer through Carbohydrate-Conjugated PROTACs

GLUTs-Facilitated Targeting BRD4 Degradation in Breast Cancer through Carbohydrate-Conjugated PROTACs

  • J Med Chem. 2025 Aug 28;68(16):17046-17064. doi: 10.1021/acs.jmedchem.5c00468.
Yunyun Gao 1,  Dan Ni 1,  Yueying Li 1,  Jia Zheng 1,  Ke Zhang 1,  Yijie Xiao 1,  Xi Tang 2,  Linfeng Li 1,  Xing Wang 3,  Yue Wei 1,  Yi He 1,  Zufeng Guo 4,  Shenyou Nie 5
Affiliations

Affiliations

  • 1 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  • 2 Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 3 Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 4 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Breast and Thyroid Surgery of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  • 5 Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention (Ministry of Education), Department of Urology of the Second Affiliated Hospital, College of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
PMID: 40815823 DOI: 10.1021/acs.jmedchem.5c00468
Abstract

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 NG-2 showing the highest degradation efficiency. Moreover, NG-2's degradation effect was GLUTs- and proteasome-dependent, with selective targeting and effective degradation in high GLUTs-expressing cells. Furthermore, NG-2 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.

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