Expanding the toolbox of covalent drug discovery

Chiral sulfonyl fluoride probes can be used to directly map ligandable tyrosines and lysines in cells, providing a rich resource of liganded sites and the first reported clickable covalent probes for most of these sites.

Chen et al. provide a new approach for developing covalent chemical probes for potential therapeutic targets, which can be used in at least three ways:

(1) newly identified sites in potential therapeutic targets can become the focus of small-molecule screens

(2) sulfonyl fluorides can serve as chemical starting points for structure-based design of ligands with improved potency and selectivity toward selected sites

(3) sulfonyl fluorides can serve as clickable occupancy probes for cellular target engagement assays.

The probes also have an alkyne handle that allows for affinity enrichment and direct identification of covalently modified protein sites. A chiral 2-methylpiperazine amide linker provides stereoselective discrimination at the level of noncovalent and covalent binding.

Using these probes, Chen et al. identified hundreds of stereoselectively modified sites in functionally diverse protein sites, many of which lack existing chemical probes or drug leads.

Overall, this work provides a resource of ligandable tyrosines and lysines that can be used to develop covalent chemical probes. Among multiple validated sites, the researchers discovered a chiral probe that modifies Y228 in the MYC binding site of the epigenetic regulator WDR5. The chiral 2-methylpiperazine amide played a dominant role in molecular recognition, and the (R) enantiomer was consistently superior in labelling WDR5 Y228.


Crystal structure PDB 8F93:

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