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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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Regulated Protein Degradation02:58

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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 Unfolded Protein Response01:37

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Encoding BRAF inhibitor functions in protein degraders.

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New BRAFV600E-targeting PROTACs were developed. These degraders avoid paradoxical ERK activation seen with first-generation BRAF inhibitors, improving their potential cancer treatment utility.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • BRAFV600E mutations drive various cancers.
  • First-generation BRAF inhibitors can paradoxically activate the MAPK pathway, limiting efficacy.
  • Targeting BRAFV600E remains a key strategy in cancer therapy.

Purpose of the Study:

  • To develop novel BRAFV600E-targeting Proteolysis Targeting Chimeras (PROTACs).
  • To investigate if modified PROTACs can overcome paradoxical MAPK pathway activation.
  • To assess the potential of new degraders for cancer treatment.

Main Methods:

  • Design and synthesis of two series of BRAFV600E-targeting PROTACs.
  • Utilizing paradox-breaker ligands as inhibitor scaffolds.
  • Assessing ERK activation in response to PROTAC treatment.

Main Results:

  • Successful development of BRAFV600E-targeting PROTACs.
  • PROTACs incorporating paradox-breaker ligands did not induce paradoxical ERK activation.
  • Demonstrated efficacy of novel degraders in preclinical models.

Conclusions:

  • BRAFV600E PROTACs can be designed to avoid paradoxical ERK activation.
  • This approach offers a potential therapeutic advantage over traditional BRAF inhibitors.
  • Novel BRAF degraders represent a promising avenue for cancer therapy.