Cancer Selective Target Degradation by Folate-Caged PROTACs

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis targeting chimeras (PROTACs) degrade intracellular proteins via the ubiquitin-proteasome system.
• Off-tissue degradation by PROTACs causes toxicity, limiting clinical use.
• Tissue-selective PROTAC activity is crucial for minimizing side effects.

Purpose of the Study:

• To develop a cancer cell-selective delivery strategy for PROTACs.
• To achieve targeted protein degradation in cancer cells while sparing normal cells.
• To create a generalizable platform for selective PROTAC applications.

Main Methods:

• Conjugating a folate group to a VHL E3 ligase ligand to create folate-PROTACs.
• Developing specific PROTACs targeting BRDs, MEKs, and ALK (folate-ARV-771, folate-MS432, folate-MS99).
• Evaluating folate receptor-dependent protein degradation in cancer cells.

Main Results:

• Folate-PROTACs demonstrated cancer cell-selective degradation of target proteins.
• BRD, MEK, and ALK degradation was observed in a folate receptor-dependent manner.
• The strategy successfully targeted proteins of interest (POIs) in cancer cells.

Conclusions:

• Folate conjugation enables selective PROTAC delivery to cancer cells.
• This approach provides a versatile platform for targeted protein degradation in oncology.
• The developed folate-PROTACs show potential for safer and more effective cancer therapies.