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Updated: Mar 27, 2026

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PROTACs in cancer therapy: targeted degradation of GPX4, PARP and epigenetic regulators

Sunny Periyasamy1, Thyla Jarrett1, Joe Truong1

  • 1Department of Chemistry, University of Massachusetts, Amherst, MA, USA.

Journal of Enzyme Inhibition and Medicinal Chemistry
|March 26, 2026
PubMed

Insights

Targeted protein degradation (TPD) using proteolysis targeting chimaeras (PROTACs) offers a novel cancer therapy approach. This review explores PROTAC design for degrading key cancer proteins and discusses challenges in clinical translation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Overexpressed proteins drive disease progression, especially in cancer.
  • Targeted protein degradation (TPD) offers a new therapeutic strategy.
  • Proteolysis targeting chimaeras (PROTACs) leverage cellular machinery for protein elimination.

Purpose of the Study:

  • To review advancements in PROTAC design and synthesis for cancer therapy.
  • To focus on PROTACs targeting poly ADP-ribose polymerases (PARPs), glutathione peroxidase 4 (GPX4), and epigenetic regulators.
  • To address challenges hindering PROTAC clinical translation.

Main Methods:

  • Review of scientific literature on PROTAC design and synthesis.
  • Analysis of PROTAC applications in targeting specific cancer-related proteins.
  • Discussion of challenges in PROTAC development and clinical implementation.

Main Results:

  • PROTACs represent a significant advancement in TPD for cancer treatment.
  • Successful PROTAC strategies have been developed for targeting PARPs, GPX4, and epigenetic regulators.
  • Key challenges include target diversification, bioavailability, stability, and efficiency.

Conclusions:

  • PROTACs hold immense promise as a novel cancer therapeutic modality.
  • Overcoming current challenges is crucial for successful clinical translation of PROTACs.
  • Further research in PROTAC design and optimization will expand their therapeutic potential.
Keywords:
Chemical synthesis of anticancer compoundsGPX4epigenetic regulatorsproteolysis targeting chimaera (PROTAC)targeted protein degradation (TPD)

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