| Industrial Drug Discovery and Academic Research using a Forkhead Translocation Assay Cell Line |
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Presentation: 5B02 Session: Imaging and High Content Screening: Valuable Tools Equally Embraced by Academia & Drug Screeners - Part 2Søren Møller, David M. Sabatini (The Whitehead Institute for Biomedical Research), and Len Pagliaro, BioImage A/S Presenting Author: Len Pagliaro, BioImage A/S - Denmark We have screened and profiled the PI3K pathway in an effort to identify novel anti-cancer compounds, and established an academic collaboration to better understand the action of various upstream effectors in this pathway. We performed a FOXO1A-EGFP Redistribution assay screen of a small molecule library, and subsequent pathway profiling of lead compounds. Following primary screening (256,000 compounds), hit profiles were deconvolved using Akt1-EGFP and Btk-PH-EGFP Redistribution assays. Hit compounds acting at multiple pathway levels were identified. Functional assays demonstrated that one compound, SCR0044001, exhibited potent (16-630 nM) and selective anti-proliferative effects in human breast and prostate cell lines. Lead optimization was performed, and increased potency efficacy has been confirmed in mouse xenograft models of breast and prostate tumors. An academic collaboration will give us the added opportunity to probe PI3K pathway function, and possible modes of action, in the Forkhead cell line using studies with a broad library of siRNAs. |