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p27 Kip1  is a cell cycle inhibitor that prevents cyclin dependent kinase (CDK)/cyclin complexes from phosphorylating their targets. p27 Kip1  is a known tumor suppressor, as the germline loss of p27 Kip1  results in sporadic pituitary formation in aged rodents, and its presence in human cancers is indicative of a poor prognosis. In addition to its role in cancer, loss of p27 Kip1  results in regenerative phenotypes in some tissues and maintenance of stem cell pluripotency, suggesting that p27 Kip1  inhibitors could be beneficial for tissue regeneration. Because p27 Kip1  is an intrinsically disordered protein, identifying direct inhibitors of the p27 Kip1  protein is difficult. Therefore, we pursued a high-throughput screening strategy to identify novel p27 Kip1  transcriptional inhibitors. We utilized a luciferase reporter plasmid driven by the  p27 Kip1   promoter to transiently transfect HeLa cells and used cyclohexamide as a positive control for non-specific inhibition. We screened a “bioactive” library consisting of 8,904 (4,359 unique) compounds, of which 830 are Food and Drug Administration (FDA) approved. From this screen, we successfully identified 111 primary hits with inhibitory effect against the promoter of  p27 Kip1  . These hits were further refined using a battery of secondary screens. Here we report four novel  p27 Kip1   transcriptional inhibitors, and further demonstrate that our most potent hit compound (IC 50  = 200 nM) Alsterpaullone 2-cyanoethyl, inhibits  p27 Kip1   transcription by preventing FoxO3a from binding to the p27 Kip1  promoter. This screen represents one of the first attempts to identify inhibitors of p27 Kip1  and may prove useful for future tissue regeneration studies.

High-Throughput Screening Reveals Alsterpaullone, 2-Cyanoethyl as a Potent p27Kip1 Transcriptional Inhibitor