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Cell Chem Biol. 2017 Sep 21;24(9):1181-1190. doi: 10.1016/j.chembiol.2017.05.024. Epub 2017 Jun 22.

Targeted Protein Degradation: from Chemical Biology to Drug Discovery.

Author information

1
Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06511, USA. Electronic address: philipp.cromm@yale.edu.
2
Department of Molecular, Cellular & Developmental Biology, Yale University, New Haven, CT 06511, USA; Department of Chemistry, Yale University, New Haven, CT 06511, USA; Department of Pharmacology, Yale University, New Haven, CT 06511, USA. Electronic address: craig.crews@yale.edu.

Abstract

Traditional pharmaceutical drug discovery is almost exclusively focused on directly controlling protein activity to cure diseases. Modulators of protein activity, especially inhibitors, are developed and applied at high concentration to achieve maximal effects. Thereby, reduced bioavailability and off-target effects can hamper compound efficacy. Nucleic acid-based strategies that control protein function by affecting expression have emerged as an alternative. However, metabolic stability and broad bioavailability represent development hurdles that remain to be overcome for these approaches. More recently, utilizing the cell's own protein destruction machinery for selective degradation of essential drivers of human disorders has opened up a new and exciting area of drug discovery. Small-molecule-induced proteolysis of selected substrates offers the potential of reaching beyond the limitations of the current pharmaceutical paradigm to expand the druggable target space.

KEYWORDS:

E3 ligase; PROTACs; hydrophobic tagging; protein degradation

PMID:
28648379
PMCID:
PMC5610075
DOI:
10.1016/j.chembiol.2017.05.024
[Indexed for MEDLINE]
Free PMC Article

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