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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic strategy for cancer by degrading intracellular proteins.
• Clinical translation of PROTACs is hindered by off-tissue toxicity due to non-specific on-target protein degradation.
• Targeted delivery strategies are crucial to enhance PROTAC efficacy and minimize side effects.

Purpose of the Study:

• To develop a tumor-selective PROTAC delivery strategy using carbohydrate conjugation.
• To investigate the efficacy of novel carbohydrate-PROTAC conjugates for targeted protein degradation in cancer cells.
• To evaluate the in vivo therapeutic potential and safety profile of the lead compound.

Main Methods:

• Design and synthesis of two series of carbohydrate and Bromodomain and Extra-Terminal motif (BET) PROTAC (ARV-771) conjugates.
• Assessment of BRD4 degradation in cancer cells, evaluating concentration- and time-dependency.
• In vitro and in vivo studies to confirm GLUTs-dependency, proteasome-dependency, tumor selectivity, and therapeutic efficacy.

Main Results:

• The synthesized carbohydrate-PROTAC conjugates effectively degraded BRD4 in a dose- and time-dependent manner.
• Compound NG-2 exhibited the highest degradation efficiency and demonstrated selective targeting and degradation in cancer cells overexpressing GLUTs.
• NG-2 significantly inhibited tumor growth in vivo with no observable significant toxicity.

Conclusions:

• Carbohydrate conjugation provides a viable strategy for achieving tumor-selective delivery of PROTACs.
• NG-2 represents a promising targeted cancer therapeutic agent with minimized off-tissue on-target degradation.
• This approach holds potential for developing safer and more effective PROTAC-based cancer therapies.