Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.
ACS Med Chem Lett
; 6(1): 53-7, 2015 Jan 08.
Article
em En
| MEDLINE
| ID: mdl-25589930
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.
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MEDLINE
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En
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2015
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Article