Due to its prevalence and the nucleophilicity of its ε-amino side chain, lysine represents an attractive target for covalent modification. Under physiological conditions, however, solvent exposed ε-amino groups exist almost entirely in the protonated form, and are thereby rendered essentially non-nucleophilic. Furthermore, in the context of covalent inhibition, lysine’s ubiquity presents a significant challenge in achieving modification site selectivity. Despite these obstacles, boronic acid carbonyls have been shown to act as reversible covalent binders of lysine residues through the formation of an imine adduct stabilized by the adjacent boronic acid. In application to the inhibition of the anti-apoptotic protein Mcl-1, these warheads, when incorporated into the scaffold of a known binder of Mcl-1, conferred an increase in both biochemical and cellular potency as well as affected their pharmacokinetic properties. Starting from a simple warhead, we sought to explore how the steric and electronic properties of these boronic acid carbonyls influence their reactivity, selectivity, and binding profiles with Mcl-1. These insights were then applied to explore the generality of boronic acid carbonyls as covalent binding motifs to target lysine residues in other proteins of interest beyond Mcl-1.

Novel, boronic-acid-based, covalent lysine inhibitors

2019 Spring National Meeting

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