Document Report Card

ID: ALA3351882

Journal: ACS Med Chem Lett

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

Authors: Goodwin NC, Cianchetta G, Burgoon HA, Healy J, Mabon R, Strobel ED, Allen J, Wang S, Hamman BD, Rawlins DB.

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.

CiteXplore: 25589930

DOI: 10.1021/ml500242y