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Publication Abstract from PubMed

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.

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.,Goodwin NC, Cianchetta G, Burgoon HA, Healy J, Mabon R, Strobel ED, Allen J, Wang S, Hamman BD, Rawlins DB ACS Med Chem Lett. 2014 Aug 7;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015, Jan 8. PMID:25589930^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.