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 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 in 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 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.