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PROteolysis TArgeting Chimeras (PROTACs)- 2 decades of research

Researchers are investigating PROteolysis TArgeting Chimeras (PROTACs) as a potential treatment for cancer, neurodegenerative diseases, and other challenging conditions. PROTACs are small molecules that utilize the ubiquitin-proteasome system to degrade specific proteins. They function by linking the target protein to an E3 ligase, triggering its degradation while the PROTAC itself is recycled for repeated use.

Different types of PROTACs include:

  1. PROteolysis Targeting AntiBodies (PROTABs)  ‍
  2. Molecular glues
  3. LYsosome-TArgeting Chimeras (LYTACs)
  4. Macrophage degradation targeting chimeras (MADTACs)

Mechanism of protein targeting by PROTACs

Protein degradation is a natural process that removes damaged or misfolded proteins. PROTACs enhance this by linking target proteins, often linked to diseases like cancer, to E3 ligases. These ligases tag the proteins with ubiquitin, signalling the ubiquitin-proteasome system to degrade them. By facilitating this interaction, PROTACs promote targeted protein degradation. (Figure-1)
Mechanism of protein targeting by PROTACs
  • A PROTAC consists of a ligand-linker-recruitment moiety, where the ligand binds the target protein, the linker ensures proper spacing, and the recruitment moiety engages E3 ligases. Initially designed to target a single protein, advancements have led to diverse PROTAC designs capable of targeting proteins through various mechanisms.
  • Dual and multi-target PROTACs: Designed to degrade multiple proteins instead of just one.
  • Peptide-based PROTACs: Use peptides instead of small molecules to target proteins lacking small molecule inhibitors.
  • bioPROTACs: Engineered E3 ligases with a protein ligand to target specific proteins.
  • CLIPTACs: Form PROTACs inside cells to improve oral drug administration using IEDDA (inverse electron demand Diels–Alder) click chemistry.
  • Click-release PROTACs (crPROTACs): Prodrug PROTACs activated at specific sites via IEDDA chemistry.
  • PHOTACs: Light-activated PROTACs for selective protein degradation with minimal off-target effects.

E3 ligases: Four E3 ligases that are of particular interest to researchers

  1. Cereblon: A 440-amino acid protein forming part of the E3 ligase complex, widely studied in PROTAC research.
  2. VHL: A substrate receptor for the CRL2 E3 ligase complex, working with elongin B/C, cullin 2, and Rbx1.
  3. IAP: A protein family (cIAP1, cIAP2, XIAP); IAP-recruiting PROTACs are called SNIPERs.
  4. MDM2: A 480-amino acid protein linked to chemotherapy resistance when overexpressed.
Figure 2. Sankey chart depicting E3 ligases (1st column), broad category of diseases (2nd column), disease targets (3rd column), and number of publications/patents (2003-2024; number against target)

PROTACs target cancer, infections, and neurodegenerative diseases.

Cancer is the primary focus of PROTAC research, followed by infectious and neurodegenerative diseases. Breast cancer, prostate cancer, and melanoma are the most studied, with recent advances in targeting ARs and ERs driving interest.

PROTACs may offer breakthroughs for neurodegenerative diseases like Alzheimer’s and Parkinson’s by targeting misfolded proteins. Successfully degrading disease-causing proteins could address root causes rather than just symptoms. Tau protein research in the PROTAC field is growing, highlighting increasing interest in this approach.

PROTACs target ARs, ERs, bromodomain proteins, and hard-to-treat proteins like KRAS and BCL2. While most progress is with AR and ER, ongoing research is expanding potential cancer treatments.

PROTACs Progress to Clinic

Since 2020, preclinical PROTAC drugs have increased over fourfold. By 2024, six PROTACs were in both Phase I and II trials, a significant milestone for a field that began in 2001.

Most PROTAC trials focus on cancer, with breast and prostate cancer being key targets.

  1. Vepdegestrant (ARV-471), by Arvinas and Pfizer for treating breast cancer, has reached Phase III.
  2. GT20029, the first topical PROTAC (Suzhou Kintor Pharmaceutical), targets AR and is in Phase II.
Preclinical trials are investigating PROTACs for proteins linked to Alzheimer’s, Parkinson’s, and Huntington’s, as well as kinases involved in HIV, hepatitis B, and autoimmune diseases. The expanding range of targets highlights PROTACs’ potential to treat challenging conditions.
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Figure 3: Number of PROTAC drugs in various stages of clinical trials (Preclinical, Phase I, Phase II, and Phase III) over the last decade

Figure 4: Various disease conditions/indications for which PROTACs are currently under development. Size of the circle corresponds to number of drugs. Data retrieved from Pharmaprojects Citeline Intelligence.

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Addressing barriers to PROTACs' clinical application

  • Despite their promise, PROTACs face challenges before widespread clinical use. A major concern is preventing off-target effects in healthy cells. Solutions like PHOTACs and CLIPTACs aim to enable precise, controlled activation to improve safety.
  • Characterization of PROTACs is challenging, as most techniques focus on binding to target proteins rather than examining interactions within live cells. This gap in knowledge hinders a full understanding of where PROTACs may fail.
  • PROTACs often don’t follow Lipinski’s rule of five, making oral administration challenging. Overcoming this requires the development of new formulations and drug delivery systems.
  • Advances in non-traditional treatments, like covalent inhibitors, show that new approaches can lead to meaningful breakthroughs. With the potential to target disease-driving proteins, investing in PROTAC research is crucial for developing innovative treatments.

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