title: Waste disposal-An attractive strategy for cancer therapy.
abstract: Targeted therapies for cancer are typically small molecules or monoclonal antibodies that act by inhibiting the activity of specific proteins that drive tumor growth. Although many of these drugs are effective in cancer patients, the response is often not durable because tumor cells develop resistance to the drugs. Another limitation of this strategy is that not all oncogenic driver proteins are "druggable" enzymes or receptors with activities that can be inhibited. Here we describe an alternative approach to targeted therapy that is based on co-opting the cellular quality-control machinery-the ubiquitin-proteasome system-to remove specific cancer-causing proteins from the cell. We first discuss examples of existing cancer drugs that work by degrading specific proteins and then review recent progress in the rational design and preclinical testing of small molecules that induce selective degradation of specific target proteins.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Jemilat
authors.identifier: 0000-0002-7379-2315
authors.initials: J
authors.lastname: Salami
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA. craig.crews@yale.edu.|Department of Chemistry, Yale University, New Haven, CT 06520, USA.|Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
authors.forename: Craig M
authors.identifier: 0000-0002-8456-2005
authors.initials: CM
authors.lastname: Crews
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D059748:Proteolysis / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009025:Morpholines; D054852:Small Molecule Libraries; D025801:Ubiquitin; C420268:Canertinib; D011505:Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex