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Related Concept Videos

Regulated Protein Degradation02:58

Regulated Protein Degradation

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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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The Proteasome02:18

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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The Proteasome01:13

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The Proteasome Structure01:17

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
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Targeted protein degradation by PROTACs.

Taavi K Neklesa1, James D Winkler1, Craig M Crews2

  • 1Arvinas, LLC, 5 Science Park, New Haven, CT 06511, United States.

Pharmacology & Therapeutics
|February 23, 2017
PubMed
Summary

Targeted protein degradation using Proteolysis-Targeting Chimeras (PROTACs) offers a novel therapeutic approach for diseases caused by abnormal protein expression, including previously undruggable targets.

Keywords:
CereblonPROTACTargeted protein degradationUndruggable proteomeVHL

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Drug Discovery

Background:

  • Targeted protein degradation is an emerging therapeutic strategy for diseases driven by aberrant protein expression.
  • PROTACs are bifunctional molecules that induce ubiquitination and proteasomal degradation of target proteins.

Purpose of the Study:

  • To highlight the advantages of PROTAC-mediated protein degradation over traditional enzyme inhibition.
  • To discuss the therapeutic potential of PROTACs for targeting currently undruggable proteins.

Main Methods:

  • Review of PROTAC technology and its mechanism of action.
  • Analysis of preclinical data demonstrating the efficacy of PROTACs in vitro and in vivo.

Main Results:

  • PROTACs can degrade proteins regardless of their enzymatic function, including the "undruggable" proteome.
  • PROTACs offer advantages such as targeting overexpressed/mutated proteins and prolonged pharmacodynamic effects.
  • High potency and selectivity can be achieved due to the catalytic nature of PROTACs.

Conclusions:

  • PROTAC technology presents a promising therapeutic modality with significant advantages over classical inhibition.
  • Delivery and bioavailability challenges for PROTACs (700-1000Da) are key hurdles for clinical translation.
  • Future research will focus on overcoming these delivery issues and demonstrating clinical proof-of-concept.