The post-translational methylation of lysine residues is a critical signaling mechanism for the control of gene expression that is part of the histone code. In all known cases, the methylation of a lysine residue on a peptide tail triggers a protein-protein interaction (PPI), and many of these interactions have been implicated as potent drivers of cancer aggression. We will report here on a class of calixarene-derived macrocycles that can recognize and bind to methylated lysine residues in the context of intact proteins and complex peptides. We have synthesized analogs that inform us on the varying roles of shape complementarity, weak interactions, and the hydrophobic effect in the successful recognition of these important motifs. Our studies have identified the first ever inhibitor of any methyllysine-triggered protein-protein interaction. We will report on our ongoing efforts to create new active compounds with improved drug-likeness, as well as the development of new biochemical assays in this area.

Methylated lysine residues and the histone code as targets for supramolecular tools

243rd National Meeting (2012)

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