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Specific small molecule inhibitors of Skp2-mediated p27 degradation.

Chemistry & biology | Dec 21, 2012

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.

Pubmed ID: 23261596 RIS Download

Mesh terms: Antineoplastic Agents | CDC2-CDC28 Kinases | Cell Cycle | Cell Line, Tumor | Cyclin-Dependent Kinase Inhibitor p27 | Humans | Models, Molecular | Neoplasms | Protein Binding | S-Phase Kinase-Associated Proteins | Small Molecule Libraries | Ubiquitination

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Associated grants

  • Agency: NIGMS NIH HHS, Id: 1R01GM099948
  • Agency: NCRR NIH HHS, Id: 1UL1RR029893
  • Agency: NCI NIH HHS, Id: 5P30CA016087
  • Agency: NHLBI NIH HHS, Id: 5T32HL007151
  • Agency: NIH HHS, Id: DP2 OD004631
  • Agency: NIH HHS, Id: DP2OD004631
  • Agency: NCI NIH HHS, Id: R01 CA176502
  • Agency: NIGMS NIH HHS, Id: R01 GM057587
  • Agency: NIGMS NIH HHS, Id: R01 GM099948
  • Agency: NCI NIH HHS, Id: R37 CA076584
  • Agency: Howard Hughes Medical Institute, Id:

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