The proposed research aims to address the gap between understanding and affecting disease by innovating in chemistry and exploring complex biology with small molecules. The research focuses on two pathways - electrophile stress-response pathways and chromatin-mediated gene regulatory pathways. These two pathways are fundamental to human disease biology, but remain poorly understood. The proposed research seeks to understand the selective interaction of subsets of electrophiles with the complex cell circuitry surrounding sulfur metabolites and how cellular electrophilic-stress response pathways might be modulated to develop new therapeutics. The proposed research also seeks to identify novel allosteric modulators of the polycomb repressive complex-2 (PRC2), the key mediator of epigenetic gene silencing, to illuminate novel cellular modes of regulation.