Discovery of MDI-114215:\nA Potent and Selective LIMK\nInhibitor To Treat Fragile X Syndrome

LIMKs are serine/threonine\nand tyrosine kinases responsible for\ncontrolling cytoskeletal dynamics as key regulators of actin stability,\nensuring synaptic health through normal synaptic bouton structure\nand function. However, LIMK1 overactivation results in abnormal dendritic\nsynaptic development that characterizes the pathogenesis of Fragile\nX Syndrome (FXS). As a result, the development of LIMK inhibitors\nrepresents an emerging disease-modifying therapeutic approach for\nFXS. We report the discovery of MDI-114215 (<b>85</b>), a novel,\npotent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite\nkinome selectivity. <b>85</b> reduces phospho-cofilin in mouse\nbrain slices and rescues impaired hippocampal long-term potentiation\nin brain slices from FXS mice. We also show that LIMK inhibitors are\neffective in reducing phospho-cofilin levels in iPSC neurons derived\nfrom FXS patients, demonstrating <b>85</b> to be a potential\ntherapeutic candidate for FXS that could have broad application to\nneurological disorders or cancers caused by LIMK1/2 overactivation\nand actin instability.