Skp2 is thought to have two critical roles in tumorigenesis. As part of SCF<sup>Skp2</sup> ubiquitin ligase, Skp2 drives the cell cycle by mediating the degradation of cell cycle proteins. Besides the proteolytic activity, Skp2 blocks p53-mediated apoptosis by outcompeting p53 for binding p300. Here we exploit the Skp2/p300 interaction as a new target for Skp2 inhibition. An affinity-based high-throughput screening of a combinatorial cyclic peptoid library identified an inhibitor that binds to Skp2 and interferes with the Skp2/p300 interaction. We show that antagonizing the Skp2/p300 interaction by the inhibitor leads to p300-mediated p53 acetylation, resulting in p53-mediated apoptosis in cancer cells, without affecting Skp2 proteolytic activity. Our results suggest that inhibition of the Skp2/p300 interaction has a great potential as a new anticancer strategy, and our Skp2 inhibitor can be developed as a chemical probe to delineate Skp2 non-proteolytic function in tumorigenesis

Chemical inhibitor of the Skp2/p300 interaction that promotes p53-mediated apoptosis

251st National Meeting (2016)

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