title: Specific small molecule inhibitors of Skp2-mediated p27 degradation.
abstract: In the ubiquitin proteasome system, the E3 ligase SCF-Skp2 and its accessory protein, Cks1, promote proliferation largely by inducing the degradation of the CDK inhibitor p27. Overexpression of Skp2 in human cancers correlates with poor prognosis, and deregulation of SCF-Skp2-Cks1 promotes tumorigenesis in animal models. We identified small molecule inhibitors specific to SCF-Skp2 activity using in silico screens targeted to the binding interface for p27. These compounds selectively inhibited Skp2-mediated p27 degradation by reducing p27 binding through key compound-receptor contacts. In cancer cells, the compounds induced p27 accumulation in a Skp2-dependent manner and promoted cell-type-specific blocks in the G1 or G2/M phases. Designing SCF-Skp2-specific inhibitors may be a novel strategy to treat cancers dependent on the Skp2-p27 axis.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Wu
authors.forename: Arsen V
authors.initials: AV
authors.lastname: Grigoryan
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.forename: Bing
authors.initials: B
authors.lastname: Hao
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cardozo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C093090:CKS1B protein, human; D044786:S-Phase Kinase-Associated Proteins; D054852:Small Molecule Libraries; D050760:Cyclin-Dependent Kinase Inhibitor p27; D042846:CDC2-CDC28 Kinases