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Related Concept Videos

Targeted Cancer Therapies02:57

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The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
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In Situ PROTAC Synthesis Enabled by Pathologically Activated Bioorthogonal Catalysis for Precision Cancer Therapy.

Dilan Ouyang1, Rongjin Yang1, Yuhang Yao1

  • 1New Cornerstone Science Laboratory, MOE Key Laboratory for Analytical Science of Food Safety and Biology, College of Chemistry, Fuzhou University, Fuzhou 350108, P. R. China.

Journal of the American Chemical Society
|October 15, 2025
PubMed
Summary
This summary is machine-generated.

This study introduces a new method for synthesizing Proteolysis-targeting chimeras (PROTACs) inside cancer cells. This approach enables targeted protein degradation, enhancing cancer treatment efficacy and reducing side effects.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Proteolysis-targeting chimeras (PROTACs) offer therapeutic potential by degrading target proteins via the ubiquitin-proteasome system.
  • Current PROTAC applications are limited by poor cell permeability and off-target effects, necessitating novel delivery and synthesis strategies.

Purpose of the Study:

  • To develop a modular strategy for in situ PROTAC synthesis within cancer cells using bioorthogonal catalysis.
  • To enhance targeted protein degradation and minimize systemic toxicity associated with conventional PROTACs.

Main Methods:

  • Developed a platform integrating glutathione-activated Click-T-Cu(II) complexes and fragmented PROTAC precursors.
  • Utilized AS1411 aptamer-conjugated liposomes for targeted delivery to nucleolin-overexpressing cancer cells.
  • Employed click chemistry for intracellular PROTAC assembly and subsequent oncoprotein degradation.

Main Results:

  • Demonstrated efficient in situ PROTAC synthesis and targeted protein degradation in vitro and in vivo.
  • Achieved robust antitumor activity with high selectivity and favorable biocompatibility.
  • Showcased modularity by degrading BRD4, PARP1, and NF-κB using diverse warheads.

Conclusions:

  • The pathologically activated bioorthogonal catalysis PROTAC (ABC-PROTAC) strategy enables precise, targeted protein degradation.
  • This approach significantly reduces systemic toxicity compared to conventional PROTACs.
  • The modular ABC-PROTAC platform holds promise for advanced cancer therapeutics.