Protein Knockdown Technology: Application of Ubiquitin Ligase to Cancer Therapy
2016
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.
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