title: Approaches to discovering drugs that regulate E3 ubiquitin ligases.
abstract: The ubiquitin-proteasome system (UPS) plays an essential role in a wide variety of cell regulatory signaling pathways. The clinical effectiveness of the proteasome inhibitor Velcade in the treatment of several human cancers underscores the importance of the UPS as a novel target area for pharmaceutical intervention. E3 ubiquitin ligases are key enzyme complexes that regulate and determine the ubiquitination of specific substrates, whose abnormal regulation has been implicated in multiple disease phenotypes. Targeting a selective E3 ligase may allow specific manipulation of distinct pathways and eventually lead to a better therapeutic index with reduced nonspecific side effects. Here, we aim to discuss the challenges of interfering with small molecules in this target class, as well as current strategies and progress in E3 ligase drug discovery.
authors.affiliation: Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. jhuang@rigel.com
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: L
authors.initials: L
authors.lastname: Tsvetkov
authors.forename: K
authors.initials: K
authors.lastname: Qu
authors.forename: S
authors.initials: S
authors.lastname: Daniel-Issakani
authors.forename: D G
authors.initials: DG
authors.lastname: Payan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D054829:RING Finger Domains; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D051017:Apoptosis Regulatory Proteins; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases