Protein Knockdown Technology: Application of Ubiquitin Ligase to Cancer Therapy

Author(s): Nobumichi Ohoka, Norihito Shibata, Takayuki Hattori, Mikihiko Naito.

Journal Name: Current Cancer Drug Targets

Volume 16 , Issue 2 , 2016

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Abstract:

Selective degradation of pathogenic proteins by small molecules in cells is a novel approach for development of therapeutic agents against various diseases, including cancer. We and others have developed a protein knockdown technology with a series of hybrid small compounds, called SNIPERs (Specific and Nongenetic IAP-dependent Protein ERasers); and peptidic chimeric molecules, called PROTACs (proteolysis-targeting chimeric molecules), which induce selective degradation of target proteins via the ubiquitin-proteasome pathway. These compounds include two different ligands connected by a linker; one is a ligand for a ubiquitin ligase and the other is a ligand for the target protein, which are expected to crosslink these proteins in cells. Theoretically, any cytosolic protein can be targeted for degradation by this technology. To date, several SNIPERs and PROTACs against various oncogenic proteins have been developed, which specifically induce polyubiquitylation and proteasomal degradation of the oncogenic proteins, resulting in cell death, growth arrest, or impaired migration of cancer cells. Thus, this protein knockdown technology has a great potential for cancer therapy.

Keywords: IAP, PROTAC (proteolysis-targeting chimeric molecule), proteasome, protein knockdown, SNIPER (Specific and Nongenetic IAP-dependent Protein ERasers), ubiquitin ligase.

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Article Details

VOLUME: 16
ISSUE: 2
Year: 2016
Page: [136 - 146]
Pages: 11
DOI: 10.2174/1568009616666151112122502
Price: $58

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