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Author Spotlight: Evaluating Biophysical Assays for Characterizing PROTACS Ternary Complexes
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Published on: January 12, 2024

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Proteolysis-Targeting Chimera (PROTAC): Current Applications and Future Directions

Gang Fan1,2, Shilin Chen3,2, Qingping Zhang4,2

  • 1Medical Research Center Affiliated Nanshan Hospital of Shenzhen University Shenzhen China.

Medcomm
|October 6, 2025
PubMed

Insights

Targeted protein degradation (TPD) revolutionizes drug discovery by actively removing disease proteins. Proteolysis-targeting chimeras (PROTACs) show significant clinical progress for challenging targets and complex diseases.

Area of Science:

  • Drug Discovery and Development
  • Molecular Biology
  • Oncology

Background:

  • Targeted protein degradation (TPD) offers a novel therapeutic strategy by actively eliminating disease-driving proteins, unlike traditional inhibition.
  • This approach expands treatment options for previously undruggable targets, including transcription factors (MYC, STAT3) and mutant oncoproteins (KRAS G12C).
  • Proteolysis-targeting chimeras (PROTACs) are the leading TPD platform, with clinical trials demonstrating significant progression.

Purpose of the Study:

  • To comprehensively review PROTAC development across various therapeutic areas.
  • To analyze key targets and evaluate the clinical progression of breakthrough PROTAC candidates.
  • To discuss challenges and future directions in PROTAC technology for complex diseases.

Main Methods:

  • Review of existing literature on PROTAC development and clinical trials.
  • Analysis of PROTAC applications targeting kinases, hormone receptors, antiapoptotic proteins, and epigenetic modulators.
  • Evaluation of clinical data for candidates like ARV-110, ARV-471, and BTK degraders.

Main Results:

  • PROTACs are advancing clinically for targets like MYC, STAT3, KRAS G12C, and BTK.
  • Successful clinical progression is noted for prostate cancer (ARV-110) and breast cancer (ARV-471) PROTACs.
  • Key challenges such as the 'hook effect' and oral bioavailability limitations are identified.

Conclusions:

  • PROTAC technology represents a paradigm shift in drug discovery, enabling the targeting of previously intractable proteins.
  • Continued innovation in delivery strategies, tissue-specific design, and E3 ligase expansion is crucial for overcoming challenges.
  • PROTACs hold significant potential for transforming the treatment of complex diseases resistant to conventional therapies.
Keywords:
PROTACclinical translationdrug discoverytarget protein degradationubiquitin–proteasome system

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