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Modular Development of Enzyme-Activatable Proteolysis Targeting Chimeras for Selective Protein Degradation and Cancer

Yanchi Chen1,2, Lina Zhang1, Lincheng Fang1

  • 1State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

JACS Au
|July 26, 2024
PubMed

Insights

Enzyme-activatable proteolysis targeting chimeras (PROTACs) selectively degrade proteins in cancer cells. This novel approach minimizes toxicity in healthy tissues, offering a safer cancer therapy.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Oncology

Background:

  • Proteolysis targeting chimeras (PROTACs) offer therapeutic potential but face challenges with on-target, off-site toxicity in normal tissues due to indiscriminate protein degradation.
  • Developing targeted PROTACs is crucial for enhancing therapeutic efficacy and patient safety.

Purpose of the Study:

  • To engineer enzyme-activatable PROTACs for cancer-specific protein degradation, thereby mitigating toxicity in healthy cells.
  • To develop a modular platform for creating cell-selective PROTACs using enzyme-responsive linkers.

Main Methods:

  • Design and synthesis of enzyme-activatable PROTACs utilizing enzyme-recognition moieties and a methylene alkoxy carbamate (MAC) self-immolative linker.
  • Evaluation of PROTACs for selective protein degradation in cancer cells versus nonmalignant cells.
  • Assessment of *in vivo* antitumor efficacy and off-tumor toxicity.

Main Results:

  • Identification of the MAC unit as a stable and efficient linker for enzyme-activatable PROTACs.
  • Development of PROTACs activated by specific cancer-associated enzymes, including a dual-enzyme-activatable PROTAC.
  • Demonstration of highly selective protein degradation in cancer cells, potent *in vivo* antitumor activity, and absence of off-tumor toxicity.
  • Proof-of-concept for broad applicability by conjugating various PROTACs and E3 ligases.

Conclusions:

  • Enzyme-activatable PROTACs represent a promising strategy to overcome the toxicity limitations of conventional PROTACs.
  • This modular approach enables targeted cancer therapy with enhanced selectivity and safety.
  • The developed platform opens new avenues for the design of next-generation targeted therapeutics.

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