Discovery of Bivalent Kinase Inhibitors via Enzyme-Templated Fragment Elaboration.
We have employed novel fragment-based screening methodology to discover bivalent kinase inhibitors with improved selectivity. Starting from a low molecular weight promiscuous kinase inhibitor, we appended a thiol for subsequent reaction with a library of acrylamide electrophiles. Enzyme-templated screening was performed to identify acrylamides that assemble into bivalent inhibitors of c-Src kinase. Upon identification of acrylamide fragments that improve the binding affinity of our lead thiol, we characterized the resulting bivalent inhibitors and identified a series of kinase inhibitors with improved potency and selectivity compared to the thiol-containing precursor. Provided that protein can be prepared free of endogenous reactive cysteines, our methodology is general and could be applied to nearly any enzyme of interest.
Departments of Medicinal Chemistry and Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Frank E
FE
Kwarcinski
Departments of Medicinal Chemistry and Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Michael E
ME
Steffey
Departments of Medicinal Chemistry and Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Christel C
CC
Fox
Departments of Medicinal Chemistry and Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Matthew B
MB
Soellner
Kinase; enzyme-templated; selectivity