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MP42:Kement:Chemical Biology Strategy Reveals Pathway-Selective Regulators of Histone 3 K27 Tri-Methylation

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Chemical Biology Strategy Reveals Pathway-Selective Regulators of Histone 3 K27 Tri-Methylation
Burcu Kement1, Michael Platchek2, Tiger Bee3, Lorena Kallal3, Pankaj Agarwal4, Xin Zeng2, Zining Wu2, Yan Liu2
1University of Pennsylvania, Philadelphia, PA; 2Screening and Compound Profiling, GSK, Collegeville, PA; 3Biological Reagents and Assay Development, GSK, Collegeville, PA; 4Computational Biology, GSK, King of Prussia, PA


Epigenetic regulation by histone methylation is crucial for proper programming of the genome during development, and dysregulation of the methylation machinery can lead to diseased states such as cancer. Homeostasis of histone methylation is balanced by the activities of histone methylases and demethylases. Although these methylases and demethylases represent logical targets for potential drug discovery, the activities of methylases and demethylases regulated in response to a complex biological stimulus is also important and not clear yet. Here, we used a set of unique chemical tools (Biologically Diverse Compound Set - BDCS), to study and manipulate histone methylation biological systems. BDCS consists of compounds that have activity against ~670 targets involved in many fundamental biological activities. With 8-10 highly selective tool compounds assigned to each target, the potential off-target effects associated with chemical probes are systemically minimized. Using BDCS, screening and profiling were done in a high-content imaging assay, which directly quantifies Histone 3 K27me3 methylation levels in HCC1806 cells using a conventional primary-secondary antibody based immunofluorescence protocol. A number of hits were identified in our study, and we observed consistent pattern of multiple hits associated with the same target. Several non-methylase/demethylase targets were identified as potential upstream regulators of Histone 3 K27me3 methylation. In summary, our study suggests that a systematically designed chemical probe library can serve as a powerful research tool when combined with phenotypic screen. Follow-up study with these findings may reveal new paths toward therapeutically useful Histone 3 K27me3 inhibitors.

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