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ACS Med Chem Lett. 2014 Aug 7;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015 Jan 8.

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

Author information

1
Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
2
Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.

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.

KEYWORDS:

DFG-out; LIM kinase 2; allosteric; noncompetitive; selective; type III kinase inhibitor

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