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Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

ABSTRACT: The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.

SUBMITTER: Goodwin NC

PROVIDER: S-EPMC4291701 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

Goodwin Nicole C NC Cianchetta Giovanni G Burgoon Hugh A HA Healy Jason J Mabon Ross R Strobel Eric D ED Allen Jason J Wang Shuli S Hamman Brian D BD Rawlins David B DB

ACS medicinal chemistry letters 20140807 1

The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away f ...[more]

PMID: 25589930

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