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Epigenetic proteins modulate a critical process in the cell that affects gene and subsequently protein expression. Analyzing epigenetic proteins at the proteome-wide level can provide critical insights into their biological mechanisms, particularly generating hypotheses around their relevance to diseases. This chapter provides an overview of the advances and application of chemical biology and mass spectrometry-based methods to interrogate complex epigenetic biology and accelerate drug development against these challenging targets. We discuss chemoproteomics, CESTA (Cellular Thermal Shift Assay), AP-MS (affinity purification mass spectrometry), interactomics, and global proteomic analysis including charting post-translation modifications, in the context of their impact on epigenetic drug discovery.

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