Metabolically Labile Fumarate Esters Impart Kinetic Selectivity to Irreversible Inhibitors.

ABSTRACT: 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 met

SUBMITTER: Zaro BW 

PROVIDER: S-EPMC5273863 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature