# A fragment-based electrophile-first approach to target histidine with aryl-fluorosulfates: application to hMcl-1

## TL;DR

Researchers developed a new method using aryl-fluorosulfates to target histidine residues in proteins, successfully identifying new covalent fragments for hMcl-1.

## Contribution

A novel electrophile-first fragment screening approach targeting histidine residues using aryl-fluorosulfates is introduced and applied to hMcl-1.

## Key findings

- Aryl-fluorosulfates can form covalent adducts with His/Lys/Tyr residues when used in fragment screening.
- New covalent fragment hits targeting hMcl-1 His 224 were identified using this approach.
- Strategies to improve the success rate of electrophile-based fragment screening for histidine residues were developed.

## Abstract

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 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 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.