title: 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 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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Balyn W
authors.initials: BW
authors.lastname: Zaro
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Landon R
authors.initials: LR
authors.lastname: Whitby
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Lum
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D002478:Cells, Cultured; D005650:Fumarates / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D005650:Fumarates; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000225:Adenine