PROTAC. Protein degradation (PROTAC and beyond)

Title: Revolutionizing Drug Discovery: PROTAC and Beyond in Protein Degradation


Protein degradation is a vital process in cellular regulation and maintaining protein homeostasis. Traditional drug discovery predominantly focuses on inhibiting protein function, but a groundbreaking approach called PROTAC (PROteolysis TArgeting Chimera) has emerged as a powerful tool for targeted protein degradation. In this blog post, we will explore the key points surrounding PROTAC and its potential beyond in protein degradation.

Key Point 1: Understanding PROTAC and Protein Degradation

  • PROTAC is a small molecule-based approach designed to induce the degradation of specific proteins.
  • It consists of two functional units: a ligand that binds to the target protein and a ligand that recruits an E3 ubiquitin ligase.
  • When the PROTAC binds to the target protein, the E3 ligase tags it with ubiquitin, leading to its degradation by the proteasome.

Key Point 2: Advantages of PROTAC in Protein Degradation

a) Targeted Protein Degradation:

  • PROTAC offers a unique advantage by specifically targeting disease-causing proteins for degradation instead of just inhibiting their activity.
  • This targeted degradation approach can be particularly useful for proteins deemed “undruggable” using traditional small molecule inhibitors.

b) Selectivity and Reduced Side Effects:

  • PROTAC-mediated protein degradation can selectively eliminate disease-causing proteins while leaving non-pathogenic proteins unaffected.
  • This selectivity holds the potential to reduce off-target effects and minimize unwanted side effects compared to traditional inhibition-based therapies.

c) Potential for Overcoming Drug Resistance:

  • PROTACs have the potential to overcome drug resistance mechanisms that arise from target mutations or adaptive responses.
  • By degrading the target protein, PROTACs can bypass resistance mechanisms that arise from traditional small molecule inhibitors binding to the target protein.

Key Point 3: Advancements and Future Opportunities Beyond PROTAC

a) Beyond E3 Ligase-Mediated Protein Degradation:

  • While PROTACs traditionally recruit E3 ubiquitin ligases, alternative strategies are emerging to harness different degradation mechanisms.
  • For example, utilizing enzymes other than E3 ligases or employing molecular glues that facilitate protein-protein interactions to promote degradation.

b) PROTACs as Therapeutic Agents:

  • Researchers are actively exploring the therapeutic potential of PROTACs in a wide range of diseases, including cancer, neurodegenerative disorders, and autoimmune conditions.
  • Early preclinical and clinical studies have shown promising results, highlighting the potential of PROTACs as a new class of therapeutics.

c) Expanding the Scope of Protein Targets:

  • PROTACs present opportunities for targeting a wide range of proteins beyond traditional drug targets, including transcription factors, scaffolding proteins, and disease-associated proteins with previously undruggable properties.


Protein degradation through PROTACs represents a revolutionary approach in drug discovery, offering a targeted and selective means of eliminating disease-causing proteins. With its potential to overcome drug resistance and minimize side effects, PROTAC-mediated protein degradation holds promise in treating a variety of diseases. As research and advancements continue to expand the scope of protein targets and approaches in degradation, we can anticipate exciting developments and new therapeutic opportunities beyond PROTAC. The future of protein degradation brings us one step closer to personalized and effective treatments for a myriad of challenging diseases.