title: 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.
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Goodwin
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cianchetta
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Burgoon
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Healy
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Ross
authors.initials: R
authors.lastname: Mabon
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Strobel
authors.affiliation: Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Allen
authors.affiliation: Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Shuli
authors.initials: S
authors.lastname: Wang
authors.affiliation: Lexicon Pharmaceuticals , 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Hamman
authors.affiliation: Lexicon Pharmaceuticals , 350 Carter Road, Princeton, New Jersey 08540, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Rawlins
keywords: DFG-out; LIM kinase 2; allosteric; noncompetitive; selective; type III kinase inhibitor