LIM kinases (LIMKs) are members of the tyrosine kinase-like family (TKL), including LIM1 and LIM2. They mainly express in brain and take part in the regulation of actin polymerization and microtubule disassembly. LIMKs can increase the cellular filamentous actin through phosphorylating and inactivating the actin depolymerizing factors ADF/cofilin. At least three different signaling pathways can activate LIMK, such as the small GTPases of the Rho family, and Ca2+/calmodulin-dependent protein kinase IV (CaMKIV). The abnormal expressions of LIMK are related to neurological disease and cancer.
Fragile X syndrome (FXS) is a genetic disorder characterized by intellectual disability and autism. Abnormal development of synapses and dendritic spines is observed in patients. The genetic alterations, which occur in FXS, lead to the increase of CGG trinucleotide repeats in the 5′ untranslated region of the RNA binding protein FMR1 (fragile X messenger ribonucleoprotein 1). Then, these changes result in the methylation of the FMR1 locus and silencing of FMR1 transcripts. Additionally, recent research reported that the inhibition of LIMK1 improved aberrant spine development in FMR1-KO mice. Therefore, LIM1 has become the target for treating FXS.
TH470 is a highly selective LIMK1/2 inhibitor.
TH470 has the 2-aminothiazole moiety as a hinge-binder and the phenylsulfamoyl moiety in the Asp–Phe–Gly (DFG)-out pocket. So, it exhibits high activities against LIMK1 and LIMK2 with IC50s of 9.8 nM and 13 nM, respectively. Moreover, The in vitro experiment proved that this inhibitor (0.05-5 μM, 12 h) inhibited neurite outgrowth in a dose-dependent manner. Thus, it indicates that TH470 is effective in modulating neuronal phenotypes mediated by the deregulation of LIMKs.
In conclusion, TH470 is a highly selective LIMK1/2 inhibitor, possessing the ability to modulateneuronal phenotypes and the potential for treating Fragile X syndrome.