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ACS Med Chem Lett. 2015 Jul 13;6(8):898-901. doi: 10.1021/acsmedchemlett.5b00167. eCollection 2015 Aug 13.

Discovery of Bivalent Kinase Inhibitors via Enzyme-Templated Fragment Elaboration.

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Departments of Medicinal Chemistry and Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.


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.


Kinase; enzyme-templated; selectivity

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