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

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Aryl-fluorosulfates are stable electrophiles that can react with Lys, Tyr, or His residues when positioned by a ligand.
• Developing novel ligands from covalent adducts is a powerful strategy, proven for Cys residues but not yet for His/Lys/Tyr.
• Existing methods lack strategies for electrophile-based fragment screening targeting His/Lys/Tyr residues.

Purpose of the Study:

• To report novel strategies for electrophile-based fragment screening targeting His/Lys/Tyr residues.
• To enhance the success rate and characterization of covalent fragment hits.
• To demonstrate the application of this strategy by identifying covalent fragments targeting hMcl-1 Histidine 224.

Main Methods:

• Deployment of an aryl-fluorosulfate fragment library with biophysical screening.
• Development of novel strategies to improve fragment screening for His/Lys/Tyr residues.
• Characterization of identified covalent fragment hits.

Main Results:

• Successful identification of initial covalent fragments using aryl-fluorosulfates.
• Novel strategies were developed and applied to enhance fragment screening success.
• Novel covalent fragment hits targeting hMcl-1 Histidine 224 were identified.

Conclusions:

• Aryl-fluorosulfate fragment screening is a viable strategy for discovering covalent ligands targeting His/Lys/Tyr residues.
• The developed methods enhance the identification and characterization of covalent fragments.
• This approach opens new avenues for drug discovery, as demonstrated by the hMcl-1 targeting example.