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

作者：Goodwin Nicole C^*; Cianchetta Giovanni; Burgoon Hugh A; Healy Jason; Mabon Ross; Strobel Eric D; Allen Jason; Wang Shuli; Hamman Brian D; Rawlins David B

来源：ACS Medicinal Chemistry Letters, 2015, 6(1): 53-57.

DOI：10.1021/ml500242y

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

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.

• 出版日期2015-1