Abstract
Protein degradation is the cell's mechanism of eliminating misfolded or unwanted proteins. The pathway by which proteins are degraded occurs through the ubiquitin-proteasome system. Ubiquitin is a small 9-kD (kDa) protein that is attached to proteins. A minimum of four ubiquitins are required for proteins to be recognized by the degradation machinery, known as the 26S proteasome. Defects in ubiquitination have been identified in a number of diseases, including cancer, neurodegenerative diseases, and metabolic disorders. We sought to exploit the delicate balance between protein synthesis and degradation to treat cancer by designing a chimeric molecule, known as Protac (Proteolysis Targeting Chimeric molecule). Protacs are heterobifunctional nanomolecules that are approximately 10 nm in size and can recruit proteins that cause cancer to the ubiquitin-proteasome machinery for degradation. In this review, we discuss the development of this novel technology for the treatment of cancer.
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Abbreviations
- AHR:
-
aryl hydrocarbon receptor
- AR:
-
androgen receptor
- ER:
-
estrogen receptor
- GFP:
-
green fluorescent protein
- HIF1:
-
hypoxia inducible factor
- MetAP-2:
-
Methionine aminopeptidase-2
- Protac:
-
Proteolysis Targeting Chimeric Molecule
- SCF:
-
Skp1-Cullin-F-box protein
- UPS:
-
ubiquitin proteasome system
- VHL:
-
Von Hippel Lindau
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Supported by the NIH (R21 CA108545) and Department of Defense (USA) Prostate Cancer Research Program (W81XWH-06-1-0192).
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Sakamoto, K. Protacs for Treatment of Cancer. Pediatr Res 67, 505–508 (2010). https://doi.org/10.1203/PDR.0b013e3181d35017
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DOI: https://doi.org/10.1203/PDR.0b013e3181d35017
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