A Fragment-Based Electrophile-First Approach to Target Histidine with Aryl-Fluorosulfates: Application to hMcl‑1

Aryl-fluorosulfates are mild electrophiles that are very
stable
in biological media and in vivo and can efficiently react with the
side chains of Lys, Tyr, or His residues, when properly juxtaposed
by a high-affinity ligand. A more powerful approach to derive novel
ligands would consist of starting from the covalent adduct and building
the ligand off those initial interactions. While this strategy has
been proven for Cys with molecular fragments containing Cys targeting
electrophiles such as acrylamides, a corresponding strategy with fluorosulfates
targeting His/Lys/Tyr residues has yet to be reported. We report here
that a fragment library of aryl-fluorosulfates, when deployed with
proper biophysical screening strategies, can identify initial covalent
fragments. We report on novel strategies to enhance the success rate
of such electrophile-based fragment screening for His/Lys/Tyr residues
and to characterize the resulting hits. As an application, we report
on novel covalent fragment hits targeting hMcl-1 His 224.