Covalent drug discovery using sulfur(VI) fluoride exchange warheads

IntroductionCovalent drug discovery has traditionally focused on targeting cysteine, but the amino acid is often absent in protein binding sites. This review makes the case to move beyond cysteine labeling using sulfur (VI) fluoride exchange (SuFEx) chemistry to expand the druggable proteome.Areas coveredRecent advances in SuFEx medicinal chemistry and chemical biology are described, which have enabled the development of covalent chemical probes that site-selectively engage amino acid residues (including tyrosine, lysine, histidine, serine, and threonine) in binding pockets. Areas covered include chemoproteomic mapping of the targetable proteome, structure-based design of covalent inhibitors and molecular glues, metabolic stability profiling, and synthetic methodologies that have expedited the delivery of SuFEx modulators.Expert opinionDespite recent innovations in SuFEx medicinal chemistry, focused preclinical research is required to ensure the field moves from early chemical probe discovery to the delivery of transformational covalent drug candidates. The authors believe that covalent drug candidates designed to engage residues beyond cysteine using sulfonyl exchange warheads will likely enter clinical trials in the coming years.

Automated summary

This review highlights the limitations of cysteine labeling in covalent drug discovery and proposes the use of SuFEx chemistry to target a broader range of amino acids. Recent advances in SuFEx medicinal chemistry and chemical biology are described, including the development of covalent chemical probes that selectively engage various amino acid residues. The authors believe that covalent drug candidates utilizing sulfonyl exchange warheads to target residues beyond cysteine have the potential to enter clinical trials in the near future.