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

ABSTRACT: 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.

SUBMITTER: Kwarcinski FE 

PROVIDER: S-EPMC4538437 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Kwarcinski Frank E FE   Steffey Michael E ME   Fox Christel C CC   Soellner Matthew B MB  

ACS medicinal chemistry letters 20150713 8

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, w  ...[more]

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