Developments in human genome sequencing technologies and functional genomic analyses present the pharmaceutical industry with many new target proteins implicated in various diseases, but for many of these proteins, there has been little prior research into their structure and function. Electrophilic fragment libraries are being increasingly adopted in drug discovery for ligandability assessments and the discovery of hit compounds. These libraries are comprised of fragments bearing moderately reactive moieties for the targeting of amino acid residues in the vicinity of protein pockets. The consequential covalent modification of the protein permits the use of mass spectrometry for rapid and robust ligand identification.<br/><br/>This field has been dominated by cysteine-targeting warheads, and photoreactive probes which crosslink to all amino acids. However, these approaches are limited by the rarity of cysteine in the proteome, and low photocrosslinking yields, respectively. Sulfonyl fluorides have recently emerged as promising warheads for targeting nucleophilic amino acid residues. Given the stability of sulfonyl fluorides under physiological conditions, and the context-specific reactivity of the functional group, warheads of this nature offer an alternative method for surveying the ligandability of the proteome.<br/><br/>We are developing a sulfur(VI) fluoride-based screening platform for ligandability assessments and hit identification. A novel synthetic methodology has been established for the efficient generation of these libraries in a plate-based format, without the requirement for purification, and these electrophilic fragments can be directly screened against proteins of therapeutic interest. Using a range of sulfur(VI) fluoride warheads, this approach has been applied to diverse panels of protein targets and various follow-up studies have validated hit compounds. It is anticipated that this screening platform will be used in parallel with alternative assessments of ligandability for emerging targets, leading to the accelerated development of chemical probes for the study of diseases, and providing starting points for the discovery of novel medicines.

Sulfur(VI) fluorides as electrophilic warheads for fragment-based ligand discovery

ACS Fall 2021

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