Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors

Electrophilic
small molecules are an important class of chemical
probes and drugs that produce biological effects by irreversibly modifying
proteins. Examples of electrophilic drugs include covalent kinase
inhibitors that are used to treat cancer and the multiple sclerosis
drug dimethyl fumarate. Optimized covalent drugs typically inactivate
their protein targets rapidly in cells, but ensuing time-dependent,
off-target protein modification can erode selectivity and diminish
the utility of reactive small molecules as chemical probes and therapeutics.
Here, we describe an approach to confer kinetic selectivity to electrophilic
drugs. We show that an analogue of the covalent Bruton’s tyrosine
kinase (BTK) inhibitor Ibrutinib bearing a fumarate ester electrophile
is vulnerable to enzymatic metabolism on a time-scale that preserves
rapid and sustained BTK inhibition, while thwarting more slowly accumulating
off-target reactivity in cell and animal models. These findings demonstrate
that metabolically labile electrophilic groups can endow covalent
drugs with kinetic selectivity to enable perturbation of proteins
and biochemical pathways with greater precision.