Covalent Targeting of Histidine Residues with Aryl Fluorosulfates: Application to Mcl‑1 BH3 Mimetics

Covalent drugs provide pharmacodynamic and pharmacokinetic
advantages
over reversible agents. However, covalent strategies have been developed
mostly to target cysteine (Cys) residues, which are rarely found in
binding sites. Among other nucleophilic residues that could be in
principle used for the design of covalent drugs, histidine (His) has
not been given proper attention despite being in principle an attractive
residue to pursue but underexplored. Aryl fluorosulfates, a mild electrophile
that is very stable in biological media, have been recently identified
as possible electrophiles to react with the side chains of Lys; however,
limited studies are available on aryl fluorosulfates’ ability
to target His residues. We demonstrate that proper incorporation of
an aryl fluorosulfate juxtaposing the electrophile with a His residue
can be used to afford rapid optimizations of His-covalent agents.
As an application, we report on His-covalent BH3 mimetics targeting
His224 of Mcl-1.