A Chemical Proteomic Atlas of the Druggable Lysine Proteome
Recent innovations in quantitative chemical proteomics have begun to unravel the reactivity and ligandability of lysines on a proteome-wide scale. Still, the aminophilic electrophiles deployed heretofore have captured only a small fraction of the ligandable lysine proteome. In this presentation, I will describe an in-depth profiling of uncharted aminophilic chemotypes that unveiled thousands of druggable lysines in human cancer cells. These experiments led to the discovery of chemoselective, reversible-covalent electrophiles, termed ‘scout' fragments, capable of capturing a remarkably broad fraction of the covalent small molecule-lysine interactions. We next mapped ‘scout' fragment-sensitive lysines to unravel the dynamic changes in primary human T cells upon activation and in peripheral blood mononuclear cells stimulated by bacterial lipopolysaccharide. I will further describe high-affinity lysine-specific small molecules that modulate the function of diverse proteins lacking small-molecule chemical probes. These findings enrich our understanding of functional and ligandable lysines in the human cancer and immune proteome and greatly expand its druggable landscape for basic and translational research.