title: Protein Knockdown Technology: Application of Ubiquitin Ligase to Cancer Therapy.
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.
authors.forename: Nobumichi
authors.initials: N
authors.lastname: Ohoka
authors.forename: Norihito
authors.initials: N
authors.lastname: Shibata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. miki-naito@nihs.go.jp.
authors.forename: Mikihiko
authors.initials: M
authors.lastname: Naito
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000378:metabolism; D015536:Down-Regulation; D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008024:Ligands; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000627:therapeutic use*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C529046:(-)-N-((2S,3R)-3-amino-2-hydroxy-4-phenyl-butyryl)-L-leucine methyl ester; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D009363:Neoplasm Proteins; D009842:Oligopeptides; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D007930:Leucine