Sulfamate Acetamides as Self-Immolative Electrophiles for Covalent Ligand-Directed Release Chemistry

Electrophiles for covalent inhibitors that are suitable
for in
vivo administration are rare. While acrylamides are prevalent in FDA-approved
covalent drugs, chloroacetamides are considered too reactive for such
purposes. We report sulfamate-based electrophiles that maintain chloroacetamide-like
geometry with tunable reactivity. In the context of the BTK inhibitor
ibrutinib, sulfamate analogues showed low reactivity with comparable
potency in protein labeling, in vitro, and cellular kinase activity
assays and were effective in a mouse model of CLL. In a second example,
we converted a chloroacetamide Pin1 inhibitor to a potent and selective
sulfamate acetamide with improved buffer stability. Finally, we show
that sulfamate acetamides can be used for covalent ligand-directed
release (CoLDR) chemistry, both for the generation of “turn-on”
probes as well as for traceless ligand-directed site-specific labeling
of proteins. Taken together, this chemistry represents a promising
addition to the list of electrophiles suitable for in vivo covalent
targeting.