Discovery of MDI-114215: A Potent and Selective LIMK Inhibitor To Treat Fragile X Syndrome

LIMKs are serine/threonine
and tyrosine kinases responsible for
controlling cytoskeletal dynamics as key regulators of actin stability,
ensuring synaptic health through normal synaptic bouton structure
and function. However, LIMK1 overactivation results in abnormal dendritic
synaptic development that characterizes the pathogenesis of Fragile
X Syndrome (FXS). As a result, the development of LIMK inhibitors
represents an emerging disease-modifying therapeutic approach for
FXS. We report the discovery of MDI-114215 (85), a novel,
potent allosteric dual-LIMK1/2 inhibitor that demonstrates exquisite
kinome selectivity. 85 reduces phospho-cofilin in mouse
brain slices and rescues impaired hippocampal long-term potentiation
in brain slices from FXS mice. We also show that LIMK inhibitors are
effective in reducing phospho-cofilin levels in iPSC neurons derived
from FXS patients, demonstrating 85 to be a potential
therapeutic candidate for FXS that could have broad application to
neurological disorders or cancers caused by LIMK1/2 overactivation
and actin instability.